Method for treating advanced non-small cell lung cancer (NSCLC) by administering a combination of a TOR kinase inhibitor and azacitidine or erlotinib

ABSTRACT

Provided herein are methods for treating or preventing advanced non-small cell lung cancer, comprising administering an effective amount of a TOR kinase inhibitor and an effective amount of erlotinib or a cytidine analog to a patient having advanced non-small cell lung cancer.

This application claims the benefit of U.S. Provisional Application No.61/603,012, filed Feb. 24, 2012, claims the benefit of U.S. ProvisionalApplication No. 61/716,424, filed Oct. 19, 2012 and claims the benefitof U.S. Provisional Application No. 61/725,805, filed Nov. 13, 2012, theentire contents of each of which are incorporated herein by reference.

1. FIELD

Provided herein are methods for treating or preventing advancednon-small cell lung cancer, comprising administering an effective amountof a TOR kinase inhibitor and an effective amount of erlotinib or acytidine analog to a patient having advanced non-small cell lung cancer.

2. BACKGROUND

The connection between abnormal protein phosphorylation and the cause orconsequence of diseases has been known for over 20 years. Accordingly,protein kinases have become a very important group of drug targets. SeeCohen, Nature, 1:309-315 (2002). Various protein kinase inhibitors havebeen used clinically in the treatment of a wide variety of diseases,such as cancer and chronic inflammatory diseases, including diabetes andstroke. See Cohen, Eur. J. Biochem., 268:5001-5010 (2001), ProteinKinase Inhibitors for the Treatment of Disease: The Promise and theProblems, Handbook of Experimental Pharmacology, Springer BerlinHeidelberg, 167 (2005).

The protein kinases are a large and diverse family of enzymes thatcatalyze protein phosphorylation and play a critical role in cellularsignaling. Protein kinases may exert positive or negative regulatoryeffects, depending upon their target protein. Protein kinases areinvolved in specific signaling pathways which regulate cell functionssuch as, but not limited to, metabolism, cell cycle progression, celladhesion, vascular function, apoptosis, and angiogenesis. Malfunctionsof cellular signaling have been associated with many diseases, the mostcharacterized of which include cancer and diabetes. The regulation ofsignal transduction by cytokines and the association of signal moleculeswith protooncogenes and tumor suppressor genes have been welldocumented. Similarly, the connection between diabetes and relatedconditions, and deregulated levels of protein kinases, has beendemonstrated. See e.g., Sridhar et al. Pharmaceutical Research,17(11):1345-1353 (2000). Viral infections and the conditions relatedthereto have also been associated with the regulation of proteinkinases. Park et al. Cell 101 (7): 777-787 (2000).

Because protein kinases regulate nearly every cellular process,including metabolism, cell proliferation, cell differentiation, and cellsurvival, they are attractive targets for therapeutic intervention forvarious disease states. For example, cell-cycle control andangiogenesis, in which protein kinases play a pivotal role are cellularprocesses associated with numerous disease conditions such as but notlimited to cancer, inflammatory diseases, abnormal angiogenesis anddiseases related thereto, atherosclerosis, macular degeneration,diabetes, obesity, and pain.

Protein kinases have become attractive targets for the treatment ofcancers. Fabbro et al., Pharmacology & Therapeutics 93:79-98 (2002). Ithas been proposed that the involvement of protein kinases in thedevelopment of human malignancies may occur by: (1) genomicrearrangements (e.g., BCR-ABL in chronic myelogenous leukemia), (2)mutations leading to constitutively active kinase activity, such asacute myelogenous leukemia and gastrointestinal tumors, (3) deregulationof kinase activity by activation of oncogenes or loss of tumorsuppressor functions, such as in cancers with oncogenic RAS, (4)deregulation of kinase activity by over-expression, as in the case ofEGFR and (5) ectopic expression of growth factors that can contribute tothe development and maintenance of the neoplastic phenotype. Fabbro etal., Pharmacology & Therapeutics 93:79-98 (2002).

The elucidation of the intricacy of protein kinase pathways and thecomplexity of the relationship and interaction among and between thevarious protein kinases and kinase pathways highlights the importance ofdeveloping pharmaceutical agents capable of acting as protein kinasemodulators, regulators or inhibitors that have beneficial activity onmultiple kinases or multiple kinase pathways. Accordingly, there remainsa need for new kinase modulators.

The protein named mTOR (mammalian target of rapamycin), which is alsocalled FRAP, RAFTI or RAPT1), is a 2549-amino acid Ser/Thr proteinkinase, that has been shown to be one of the most critical proteins inthe mTOR/PI3K/Akt pathway that regulates cell growth and proliferation.Georgakis and Younes Expert Rev. Anticancer Ther. 6(1):131-140 (2006).mTOR exists within two complexes, mTORC1 and mTORC2. While mTORC1 issensitive to rapamycin analogs (such as temsirolimus or everolimus),mTORC2 is largely rapamycin-insensitive. Notably, rapamycin is not a TORkinase inhibitor. Several mTOR inhibitors have been or are beingevaluated in clinical trials for the treatment of cancer. Temsirolimuswas approved for use in renal cell carcinoma in 2007 and sirolimus wasapproved in 1999 for the prophylaxis of renal transplant rejection.Everolimus was approved in 2009 for renal cell carcinoma patients thathave progressed on vascular endothelial growth factor receptorinhibitors, in 2010 for subependymal giant cell astrocytoma (SEGA)associated with tuberous sclerosis (TS) in patients who require therapybut are not candidates for surgical resection, and in 2011 forprogressive neuroendocrine tumors of pancreatic origin (PNET) inpatients with unresectable, locally advanced or metastatic disease.There remains a need for TOR kinase inhibitors that inhibit both mTORC1and mTORC2 complexes.

Citation or identification of any reference in Section 2 of thisapplication is not to be construed as an admission that the reference isprior art to the present application.

3. SUMMARY

Provided herein are methods for treating or preventing advancednon-small cell lung cancer, comprising administering an effective amountof a TOR kinase inhibitor and an effective amount of erlotinib or acytidine analog to a patient having advanced non-small cell lung cancer.

In certain embodiments, provided herein are methods for achieving aResponse Evaluation Criteria in Solid Tumors (for example, RECIST 1.1)of complete response, partial response or stable disease in a patienthaving advanced non-small cell lung cancer, comprising administering aneffective amount of a TOR kinase inhibitor in combination with aneffective amount of erlotinib or a cytidine analog to said patient.

In certain embodiments, provided herein are methods for increasingsurvival without tumor progression of a patient having advancednon-small cell lung cancer, comprising administering an effective amountof a TOR kinase inhibitor in combination with an effective amount oferlotinib or a cytidine analog to said patient.

In certain embodiments, the TOR kinase inhibitor is a compound asdescribed herein.

The present embodiments can be understood more fully by reference to thedetailed description and examples, which are intended to exemplifynon-limiting embodiments.

4. BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts the viability dose-response curves and isobolograms forCompound 1 and 5-azacitidine for H1755 cells, and the synergy seen forthe combination treatment, for 2 combination ratios.

FIG. 2 depicts the viability dose-response curves and isobolograms forCompound 1 and erlotinib for H1755 cells, and the synergy seen for thecombination treatment, for 2 combination ratios.

FIG. 3 depicts: A. Impact of sequence of addition and ratio on CIvalues. CI values of all combinations from each of the three sequencesof addition were compared by t-test. Sim: Simultaneously addition ofboth compounds; SeqM1: Compound 1 first followed by addition ofazacitidine; SeqM2: azacitidine first followed by addition ofCompound 1. B. Different ratios of azacitidine and Compound 1 do notsignificantly impact CI values in SeqM2 addition.

FIG. 4 depicts: A. Sequence of addition has no impact on CI values forCompound 1 and erlotinib combination. CI values of all combinations fromeach of the three sequences of addition were compared by t-test. Sim:Simultaneously addition of both compounds; SeqM1: Compound 1 firstfollowed by addition of azacitidine; SeqM2: azacitidine first followedby addition of Compound 1. B. Different ratios of azacitidine andCompound 1 significantly impact CI values.

FIGS. 5A-D depict combination indices of erlotinib treatment incombination with Compound 1 in various cell lines, at variousconcentrations. FIG. 1A depicts the combination indices in A549 cellline. FIG. 1B shows the combination indices in H1975 cell line. FIG. 1Cdemonstrates the combination indices in HCC95 cell line. FIG. 1D showsthe combination indices in H1650 cell line.

FIG. 6 depicts cell cycle analysis in A549 cell line treated witherlotinib, Compound 1, or their combination.

FIGS. 7A and 7B show a biomarker analysis using Western blotting. Celllines were treated with erlotinib, Compound 1, or their combination for1 or 3 days. Cell lysates were produced and 30 μg protein subjected toSDS-PAGE and Western blotting. The data for cell lines A549 and H1975 isshown in FIG. 7A. The data for cell lines H1650 and HCC95 is shown inFIG. 7B.

FIG. 8 shows the anti-tumor activity of Compound 1 or erlotinib, whenadministered orally as single agents, and in combination in A549xenografts.

FIG. 9 shows the anti-tumor activity of Compound 1 and erlotinib, whenadministered orally as single agents, and in combination, in H1975xenografts.

5. DETAILED DESCRIPTION 5.1 Definitions

An “alkyl” group is a saturated, partially saturated, or unsaturatedstraight chain or branched non-cyclic hydrocarbon having from 1 to 10carbon atoms, typically from 1 to 8 carbons or, in some embodiments,from 1 to 6, 1 to 4, or 2 to 6 or carbon atoms. Representative alkylgroups include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl and-n-hexyl; while saturated branched alkyls include -isopropyl,-sec-butyl, -isobutyl, -tert-butyl, -isopentyl, 2-methylpentyl,3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl and the like. Examplesof unstirred alkyl groups include, but are not limited to, vinyl, allyl,—CH═CH(CH₃), —CH═C(CH₃)₂, —C(CH₃)═CH₂, —C(CH₃)═CH(CH₃), —C(CH₂CH₃)═CH₂,—C≡H, —C≡C(CH₃), —C≡C(CH₂CH₃), —CH₂C≡CH, —CH₂C≡C(CH₃) and—CH₂C≡C(CH₇CH₃), among others. An alkyl group can be substituted orunsubstituted. In certain embodiments, when the alkyl groups describedherein are said to be “substituted,” they may be substituted with anysubstituent or substituents as those found in the exemplary compoundsand embodiments disclosed herein, as well as halogen (chloro, iodo,bromo, or fluoro); hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino;carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine;guanidine; enamine; aminocarbonyl; acylamino; phosphonato; phosphine;thiocarbonyl; sulfonyl; sulfone; sulfonamide; ketone; aldehyde; ester;urea; urethane; oxime; hydroxylamine; alkoxyamine; aralkoxyamine;N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate;isothiocyanate; cyanate; thiocyanate; B(OH)₂, or O(alkyl)aminocarbonyl.

An “alkenyl” group is a straight chain or branched non-cyclichydrocarbon having from 2 to 10 carbon atoms, typically from 2 to 8carbon atoms, and including at least one carbon-carbon double bond.Representative straight chain and branched (C₂-C₈)alkenyls include-vinyl, -allyl, -1-butenyl, -2-butenyl, -isobutylenyl, -1-pentenyl,-2-pentenyl, -3-methyl-1-butenyl, -2-methyl-2-butenyl,-2,3-dimethyl-2-butenyl, -1-hexenyl, -2-hexenyl, -3-hexenyl,-1-heptenyl, -2-heptenyl, -3-heptenyl, -1-octenyl, -2-octenyl,-3-octenyl and the like. The double bond of an alkenyl group can beunconjugated or conjugated to another unsaturated group. An alkenylgroup can be unsubstituted or substituted.

A “cycloalkyl” group is a saturated, partially saturated, or unsaturatedcyclic alkyl group of from 3 to 10 carbon atoms having a single cyclicring or multiple condensed or bridged rings which can be optionallysubstituted with from 1 to 3 alkyl groups. In some embodiments, thecycloalkyl group has 3 to 8 ring members, whereas in other embodimentsthe number of ring carbon atoms ranges from 3 to 5, 3 to 6, or 3 to 7.Such cycloalkyl groups include, by way of example, single ringstructures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl,2-methylcyclooctyl, and the like, or multiple or bridged ring structuressuch as adamantyl and the like. Examples of unsaturated cycloalkylgroups include cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl,pentadienyl, hexadienyl, among others. A cycloalkyl group can besubstituted or unsubstituted. Such substituted cycloalkyl groupsinclude, by way of example, cyclohexanone and the like.

An “aryl” group is an aromatic carbocyclic group of from 6 to 14 carbonatoms having a single ring (e.g., phenyl) or multiple condensed rings(e.g., naphthyl or anthryl). In some embodiments, aryl groups contain6-14 carbons, and in others from 6 to 12 or even 6 to 10 carbon atoms inthe ring portions of the groups. Particular aryls include phenyl,biphenyl, naphthyl and the like. An aryl group can be substituted orunsubstituted. The phrase “aryl groups” also includes groups containingfused rings, such as fused aromatic-aliphatic ring systems (e.g.,indanyl, tetrahydronaphthyl, and the like).

A “heteroaryl” group is an aryl ring system having one to fourheteroatoms as ring atoms in a heteroaromatic ring system, wherein theremainder of the atoms are carbon atoms. In some embodiments, heteroarylgroups contain 5 to 6 ring atoms, and in others from 6 to 9 or even 6 to10 atoms in the ring portions of the groups. Suitable heteroatomsinclude oxygen, sulfur and nitrogen. In certain embodiments, theheteroaryl ring system is monocyclic or bicyclic. Non-limiting examplesinclude but are not limited to, groups such as pyrrolyl, pyrazolyl,imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl,pyrolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl,benzothiophenyl, furanyl, benzofuranyl (for example,isobenzofuran-1,3-diimine), indolyl, azaindolyl (for example,pyrrolopyridyl or 1H-pyrrolo[2,3-b]pyridyl), indazolyl, benzimidazolyl(for example, 1H-benzo[d]imidazolyl), imidazopyridyl (for example,azabenzimidazolyl, 3H-imidazo[4,5-b]pyridyl or1H-imidazo[4,5-b]pyridyl), pyrazolopyridyl, triazolopyridyl,benzotriazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl,isoxazolopyridyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl,guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl,and quinazolinyl groups.

A “heterocyclyl” is an aromatic (also referred to as heteroaryl) ornon-aromatic cycloalkyl in which one to four of the ring carbon atomsare independently replaced with a heteroatom from the group consistingof O, S and N. In some embodiments, heterocyclyl groups include 3 to 10ring members, whereas other such groups have 3 to 5, 3 to 6, or 3 to 8ring members. Heterocyclyls can also be bonded to other groups at anyring atom (i.e., at any carbon atom or heteroatom of the heterocyclicring). A heterocyclylalkyl group can be substituted or unsubstituted.Heterocyclyl groups encompass unsaturated, partially saturated andsaturated ring systems, such as, for example, imidazolyl, imidazolinyland imidazolidinyl groups. The phrase heterocyclyl includes fused ringspecies, including those comprising fused aromatic and non-aromaticgroups, such as, for example, benzotriazolyl,2,3-dihydrobenzo[1,4]dioxinyl, and benzo[1,3]dioxolyl. The phrase alsoincludes bridged polycyclic ring systems containing a heteroatom suchas, but not limited to, quinuclidyl. Representative examples of aheterocyclyl group include, but are not limited to, aziridinyl,azetidinyl, pyrrolidyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl,tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, furanyl, thiophenyl,pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl,triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiazolinyl,isothiazolyl, thiadiazolyl, oxadiazolyl, piperidyl, piperazinyl,morpholinyl, thiomorpholinyl, tetrahydropyranyl (for example,tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, oxathiane, dioxyl,dithianyl, pyranyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl,triazinyl, dihydropyridyl, dihydrodithiinyl, dihydrodithionyl,homopiperazinyl, quinuclidyl, indolyl, indolinyl, isoindolyl, azaindolyl(pyrrolopyridyl), indazolyl, indolizinyl, benzotriazolyl,benzimidazolyl, benzofuranyl, benzothiophenyl, benzthiazolyl,benzoxadiazolyl, benzoxazinyl, benzodithiinyl, benzoxathiinyl,benzothiazinyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl,benzo[1,3]dioxolyl, pyrazolopyridyl, imidazopyridyl (azabenzimidazolyl;for example, 1H-imidazo[4,5-b]pyridyl, or1H-imidazo[4,5-b]pyridin-2(3H)-onyl), triazolopyridyl, isoxazolopyridyl,purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl,quinolizinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl,naphthyridinyl, pteridinyl, thianaphthalenyl, dihydrobenzothiazinyl,dihydrobenzofuranyl, dihydroindolyl, dihydrobenzodioxinyl,tetrahydroindolyl, tetrahydroindazolyl, tetrahydrobenzimidazolyl,tetrahydrobenzotriazolyl, tetrahydropyrrolopyridyl,tetrahydropyrazolopyridyl, tetrahydroimidazopyridyl,tetrahydrotriazolopyridyl, and tetrahydroquinolinyl groups.Representative substituted heterocyclyl groups may be mono-substitutedor substituted more than once, such as, but not limited to, pyridyl ormorpholinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted, ordisubstituted with various substituents such as those listed below.

A “cycloalkylalkyl” group is a radical of the formula:-alkyl-cycloalkyl, wherein alkyl and cycloalkyl are defined above.Substituted cycloalkylalkyl groups may be substituted at the alkyl, thecycloalkyl, or both the alkyl and the cycloalkyl portions of the group.Representative cycloalkylalkyl groups include but are not limited tocyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl,and cyclohexylpropyl. Representative substituted cycloalkylalkyl groupsmay be mono-substituted or substituted more than once.

An “aralkyl” group is a radical of the formula: -alkyl-aryl, whereinalkyl and aryl are defined above. Substituted aralkyl groups may besubstituted at the alkyl, the aryl, or both the alkyl and the arylportions of the group. Representative aralkyl groups include but are notlimited to benzyl and phenethyl groups and fused (cycloalkylaryl)alkylgroups such as 4-ethyl-indanyl.

A “heterocyclylalkyl” group is a radical of the formula:-alkyl-heterocyclyl, wherein alkyl and heterocyclyl are defined above.Substituted heterocyclylalkyl groups may be substituted at the alkyl,the heterocyclyl, or both the alkyl and the heterocyclyl portions of thegroup. Representative heterocylylalkyl groups include but are notlimited to 4-ethyl-morpholinyl, 4-propylmorpholinyl, furan-2-yl methyl,furan-3-yl methyl, pyridine-3-yl methyl,(tetrahydro-2H-pyran-4-yl)methyl, (tetrahydro-2H-pyran-4-yl)ethyl,tetrahydrofuran-2-yl methyl, tetrahydrofuran-2-yl ethyl, and indol-2-ylpropyl.

A “halogen” is fluorine, chlorine, bromine or iodine.

A “hydroxyalkyl” group is an alkyl group as described above substitutedwith one or more hydroxy groups.

An “alkoxy” group is —O-(alkyl), wherein alkyl is defined above.

An “alkoxyalkyl” group is -(alkyl)-O-(alkyl), wherein alkyl is definedabove.

An “amino” group is a radical of the formula: —NH₂.

An “alkylamino” group is a radical of the formula: —NH-alkyl or—N(alkyl)₂, wherein each alkyl is independently as defined above.

A “carboxy” group is a radical of the formula: —C(O)OH.

An “aminocarbonyl” group is a radical of the formula: —C(O)N(R^(#))₂,—C(O)NH(R^(#)) or —C(O)NH₂, wherein each R^(#) is independently asubstituted or unsubstituted alkyl, cycloalkyl, aryl, aralkyl,heterocyclyl or heterocyclyl group as defined herein.

An “acylamino” group is a radical of the formula: —NHC(O)(R^(#)) or—N(alkyl)C(O)(R^(#)), wherein each alkyl and R^(#) are independently asdefined above.

An “alkylsulfonylamino” group is a radical of the formula: —NHSO₂(R^(#))or —N(alkyl)SO₂(R^(#)), wherein each alkyl and R^(#) are defined above.

A “urea” group is a radical of the formula: —N(alkyl)C(O)N(R^(#))₂,—N(alkyl)C(O)NH(R^(#)), —N(alkyl)C(O)NH₂, —NHC(O)N(R^(#))₂,—NHC(O)NH(R^(#)), or —NH(CO)NHR^(#), wherein each alkyl and R^(#) areindependently as defined above.

When the groups described herein, with the exception of alkyl group aresaid to be “substituted,” they may be substituted with any appropriatesubstituent or substituents. Illustrative examples of substituents arethose found in the exemplary compounds and embodiments disclosed herein,as well as halogen (chloro, iodo, bromo, or fluoro); alkyl; hydroxyl;alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol;thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl;acylamino; phosphonato; phosphine; thiocarbonyl; sulfonyl; sulfone;sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime;hydroxylamine; alkoxyamine; aralkoxyamine; N-oxide; hydrazine;hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate;thiocyanate; oxygen (═O); B(OH)₂, O(alkyl)aminocarbonyl; cycloalkyl,which may be monocyclic or fused or non-fused polycyclic (e.g.,cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), or a heterocyclyl,which may be monocyclic or fused or non-fused polycyclic (e.g.,pyrrolidyl, piperidyl, piperazinyl, morpholinyl, or thiazinyl);monocyclic or fused or non-fused polycyclic aryl or heteroaryl (e.g.,phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl,oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl,pyridinyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl,pyrimidinyl, benzimidazolyl, benzothiophenyl, or benzofuranyl) aryloxy;aralkyloxy; heterocyclyloxy; and heterocyclyl alkoxy.

As used herein, the term “pharmaceutically acceptable salt(s)” refers toa salt prepared from a pharmaceutically acceptable non-toxic acid orbase including an inorganic acid and base and an organic acid and base.Suitable pharmaceutically acceptable base addition salts of the TORkinase inhibitors include, but are not limited to metallic salts madefrom aluminum, calcium, lithium, magnesium, potassium, sodium and zincor organic salts made from lysine, N,N′-dibenzylethylenediamine,chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine(N-methylglucamine) and procaine. Suitable non-toxic acids include, butare not limited to, inorganic and organic acids such as acetic, alginic,anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethenesulfonic, formic, fumaric, furoic, galacturonic, gluconic,glucuronic, glutamic, glycolic, hydrobromic, hydrochloric, isethionic,lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic,pantothenic, phenylacetic, phosphoric, propionic, salicylic, stearic,succinic, sulfanilic, sulfuric, tartaric acid, and p-toluenesulfonicacid. Specific non-toxic acids include hydrochloric, hydrobromic,phosphoric, sulfuric, and methanesulfonic acids. Examples of specificsalts thus include hydrochloride and mesylate salts. Others arewell-known in the art, see for example, Remington's PharmaceuticalSciences, 18^(th) eds., Mack Publishing, Easton Pa. (1990) or Remington:The Science and Practice of Pharmacy, 19^(th) eds., Mack Publishing,Easton Pa. (1995).

As used herein and unless otherwise indicated, the term “clathrate”means a TOR kinase inhibitor, or a salt thereof, in the form of acrystal lattice that contains spaces (e.g., channels) that have a guestmolecule (e.g., a solvent or water) trapped within or a crystal latticewherein a TOR kinase inhibitor is a guest molecule.

As used herein and unless otherwise indicated, the term “solvate” meansa TOR kinase inhibitor, or a salt thereof, that further includes astoichiometric or non-stoichiometric amount of a solvent bound bynon-covalent intermolecular forces. In one embodiment, the solvate is ahydrate.

As used herein and unless otherwise indicated, the term “hydrate” meansa TOR kinase inhibitor, or a salt thereof, that further includes astoichiometric or non-stoichiometric amount of water bound bynon-covalent intermolecular forces.

As used herein and unless otherwise indicated, the term “prodrug” meansa TOR kinase inhibitor derivative that can hydrolyze, oxidize, orotherwise react under biological conditions (in vitro or in vivo) toprovide an active compound, particularly a TOR kinase inhibitor.Examples of prodrugs include, but are not limited to, derivatives andmetabolites of a TOR kinase inhibitor that include biohydrolyzablemoieties such as biohydrolyzable amides, biohydrolyzable esters,biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzableureides, and biohydrolyzable phosphate analogues. In certainembodiments, prodrugs of compounds with carboxyl functional groups arethe lower alkyl esters of the carboxylic acid. The carboxylate estersare conveniently formed by esterifying any of the carboxylic acidmoieties present on the molecule. Prodrugs can typically be preparedusing well-known methods, such as those described by Burger's MedicinalChemistry and Drug Discovery 6^(th) ed. (Donald J. Abraham ed., 2001,Wiley) and Design and Application of Prodrugs (H. Bundgaard ed., 1985,Harwood Academic Publishers Gmfh).

As used herein and unless otherwise indicated, the term “stereoisomer”or “stereomerically pure” means one stereoisomer of a TOR kinaseinhibitor that is substantially free of other stereoisomers of thatcompound. For example, a stereomerically pure compound having one chiralcenter will be substantially free of the opposite enantiomer of thecompound. A stereomerically pure compound having two chiral centers willbe substantially free of other diastereomers of the compound. A typicalstereomerically pure compound comprises greater than about 80% by weightof one stereoisomer of the compound and less than about 20% by weight ofother stereoisomers of the compound, greater than about 90% by weight ofone stereoisomer of the compound and less than about 10% by weight ofthe other stereoisomers of the compound, greater than about 95% byweight of one stereoisomer of the compound and less than about 5% byweight of the other stereoisomers of the compound, or greater than about97% by weight of one stereoisomer of the compound and less than about 3%by weight of the other stereoisomers of the compound. The TOR kinaseinhibitors can have chiral centers and can occur as racemates,individual enantiomers or diastereomers, and mixtures thereof. All suchisomeric forms are included within the embodiments disclosed herein,including mixtures thereof. The use of stereomerically pure forms ofsuch TOR kinase inhibitors, as well as the use of mixtures of thoseforms are encompassed by the embodiments disclosed herein. For example,mixtures comprising equal or unequal amounts of the enantiomers of aparticular TOR kinase inhibitor may be used in methods and compositionsdisclosed herein. These isomers may be asymmetrically synthesized orresolved using standard techniques such as chiral columns or chiralresolving agents. See, e.g., Jacques, J., et al., Enantiomers, Racematesand Resolutions (Wiley-Interscience, New York, 1981); Wilen, S. H., etal., Tetrahedron 33:2725 (1977); Eliel, E. L., Stereochemistry of CarbonCompounds (McGraw-Hill, NY, 1962); and Wilen, S. H., Tables of ResolvingAgents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of NotreDame Press, Notre Dame, Ind., 1972).

It should also be noted the TOR kinase inhibitors can include E and Zisomers, or a mixture thereof, and cis and trans isomers or a mixturethereof. In certain embodiments, the TOR kinase inhibitors are isolatedas either the cis or trans isomer. In other embodiments, the TOR kinaseinhibitors are a mixture of the cis and trans isomers.

“Tautomers” refers to isomeric forms of a compound that are inequilibrium with each other. The concentrations of the isomeric formswill depend on the environment the compound is found in and may bedifferent depending upon, for example, whether the compound is a solidor is in an organic or aqueous solution. For example, in aqueoussolution, pyrazoles may exhibit the following isomeric forms, which arereferred to as tautomers of each other:

As readily understood by one skilled in the art, a wide variety offunctional groups and other structures may exhibit tautomerism and alltautomers of the TOR kinase inhibitors are within the scope of thepresent invention.

It should also be noted the TOR kinase inhibitors can contain unnaturalproportions of atomic isotopes at one or more of the atoms. For example,the compounds may be radiolabeled with radioactive isotopes, such as forexample tritium (³H), iodine-125 (¹²⁵I), sulfur-35 (³⁵S), or carbon-14(¹⁴C), or may be isotopically enriched, such as with deuterium (²H),carbon-13 (¹³C), or nitrogen-15 (¹⁵N). As used herein, an “isotopologue”is an isotopically enriched compound. The term “isotopically enriched”refers to an atom having an isotopic composition other than the naturalisotopic composition of that atom. “Isotopically enriched” may alsorefer to a compound containing at least one atom having an isotopiccomposition other than the natural isotopic composition of that atom.The term “isotopic composition” refers to the amount of each isotopepresent for a given atom. Radiolabeled and isotopically encrichedcompounds are useful as therapeutic agents, e.g., cancer andinflammation therapeutic agents, research reagents, e.g., binding assayreagents, and diagnostic agents, e.g., in vivo imaging agents. Allisotopic variations of the TOR kinase inhibitors as described herein,whether radioactive or not, are intended to be encompassed within thescope of the embodiments provided herein. In some embodiments, there areprovided isotopologues of the TOR kinase inhibitors, for example, theisotopologues are deuterium, carbon-13, or nitrogen-15 enriched TORkinase inhibitors.

“Treating” as used herein, means an alleviation, in whole or in part, ofadvanced non-small cell lung cancer or a symptom associated withadvanced non-small cell lung cancer, or slowing, or halting of furtherprogression or worsening of those symptoms.

“Preventing” as used herein, means the prevention of the onset,recurrence or spread, in whole or in part, of advanced non-small celllung cancer, or a symptom thereof.

The term “effective amount” in connection with an TOR kinase inhibitor,erlotinib or a cytidine analog means an amount alone or in combinationcapable of alleviating, in whole or in part, a symptom associated withadvanced non-small cell lung cancer, or slowing or halting furtherprogression or worsening of those symptoms, or treating or preventingadvanced non-small cell lung cancer in a subject having or at risk forhaving advanced non-small cell lung cancer. The effective amount of theTOR kinase inhibitor, erlotinib or a cytidine analog, for example in apharmaceutical composition, may be at a level that will exercise thedesired effect; for example, about 0.005 mg/kg of a subject's bodyweight to about 100 mg/kg of a patient's body weight in unit dosage forboth oral and parenteral administration.

In one embodiment, erlotinib is TARCEVA®.

In certain embodiments, the cytidine analog is 5-azacitidine (also knownas 4-amino-1-β-D-ribofuranosyl-1,3,5-triazin-2(1H)-one; National ServiceCenter designation NSC-102816; CAS Registry Number 320-67-2;azacitidine; Aza and AZA; and currently marketed as VIDAZA®). In certainembodiments, the cytidine analog is 2′-deoxy-5-azacytidine (also knownas 5-aza-2′-deoxycytidine, decitabine, 5-aza-CdR, Dac, and DAC, andcurrently marketed as DACOGEN®). In certain embodiments, the cytidineanalog is, for example: 1-β-D-arabinofuranosylcytosine (Cytarabine orara-C); pseudoiso-cytidine (psi ICR); 5-fluoro-2′-deoxycytidine (FCdR);2′-deoxy-2′,2′-difluorocytidine (Gemcitabine);5-aza-2′-deoxy-2′,2′-difluorocytidine; 5-aza-2′-deoxy-2′-fluorocytidine;1-β-D-ribofuranosyl-2(1H)-pyrimidinone (Zebularine);2′,3′-dideoxy-5-fluoro-3′-thiacytidine (Emtriva); 2′-cyclocytidine(Ancitabine); 1-β-D-arabinofuranosyl-5-azacytosine (Fazarabine orara-AC); 6-azacytidine (6-aza-CR); 5,6-dihydro-5-azacytidine(dH-aza-CR); N⁴ pentyloxy-carbonyl-5′-deoxy-5-fluorocytidine(Capecitabine); N⁴ octadecyl-cytarabine; elaidic acid cytarabine; or aconjugated compound comprising a cytidine analog and a fatty acid (e.g.,an azacitidine-fatty acid conjugate, including, but not limited to,CP-4200 (Clavis Pharma ASA) or a compound disclosed in WO 2009/042767,such as aza-C-5′-petroselinic acid ester or aza-C-5′-petroselaidic acidester).

In certain embodiments, cytidine analogs provided herein includeesterified derivatives of cytidine analogs, such as, e.g., esterifiedderivatives of 5-azacitidine. In particular embodiments, esterifiedderivatives are cytidine analogs that contain an ester moiety (e.g., anacetyl group) at one or more positions on the cytidine analog molecule.Esterified derivatives may be prepared by any method known in the art.In certain embodiments, esterified derivatives of a cytidine analogserve as prodrugs of the cytidine analog, such that, e.g., followingadministration of an esterified derivative, the derivative isdeacetylated in vivo to yield the cytidine analog. A particularembodiment herein provides 2′,3′,5′-triacetyl-5-azacytidine (TAC), whichpossesses favorable physical-chemical and therapeutic properties. See,e.g., International Publication No. WO 2008/092127 (InternationalApplication No. PCT/US2008/052124); Ziemba, A. J., et al., “Developmentof Oral Demethylating Agents for the Treatment of MyelodysplasticSyndrome” (Abstract No. 3369), In: Proceedings of the 100th AnnualMeeting of the American Association for Cancer Research; 2009 Apr.18-22; Denver, Co. Philadelphia (PA): AACR; 2009 (both of which areincorporated by reference herein in their entireties).

In certain embodiments, the cytidine analogs provided herein include anycompound which is structurally related to cytidine or deoxycytidine andfunctionally mimics and/or antagonizes the action of cytidine ordeoxycytidine. Certain embodiments herein provide salts, cocrystals,solvates (e.g., hydrates), complexes, prodrugs, precursors, metabolites,and/or other derivatives of the cytidine analogs provided herein. Forexample, particular embodiments provide salts, cocrystals, solvates(e.g., hydrates), complexes, precursors, metabolites, and/or otherderivatives of 5-azacitidine. Certain embodiments provide cytidineanalogs that are not salts, cocrystals, solvates (e.g., hydrates), orcomplexes of the cytidine analogs provided herein. For example,particular embodiments provide 5-azacitidine in a non-ionized,non-solvated (e.g., anhydrous), non-complexed form. Certain embodimentsherein provide mixtures of two or more cytidine analogs provided herein.

Cytidine analogs referred to herein may be prepared using syntheticmethods and procedures referenced herein or otherwise available in theliterature. For example, particular methods for synthesizing5-azacitidine are taught in, e.g., U.S. Pat. No. 7,038,038 andreferences discussed therein, each of which is incorporated herein byreference. 5-Azacitidine is also available from Celgene Corporation,Warren, N.J. Other cytidine analogs provided herein may be preparedusing previously disclosed synthetic procedures available to a person ofordinary skill in the art.

As used herein, and unless otherwise specified, the term “in combinationwith” includes the administration of two or more therapeutic agentssimultaneously, concurrently, or sequentially within no specific timelimits unless otherwise indicated. In one embodiment, a TOR kinaseinhibitor is administered in combination with erlotinib or a cytidineanalog. In one embodiment, the agents are present in the cell or in thesubject's body at the same time or exert their biological or therapeuticeffect at the same time. In one embodiment, the therapeutic agents arein the same composition or unit dosage form. In other embodiments, thetherapeutic agents are in separate compositions or unit dosage forms. Incertain embodiments, a first agent can be administered prior to (e.g., 5minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before),essentially concomitantly with, or subsequent to (e.g., 5 minutes, 15minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks,4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) theadministration of a second therapeutic agent, or any combinationthereof. For example, in one embodiment, the first agent can beadministered prior to the second therapeutic agent, for e.g. 1 week. Inanother, the first agent can be administered prior to (for example 1 dayprior) and then concomitant with the second therapeutic agent.

The terms “patient” and “subject” as used herein include an animal,including, but not limited to, an animal such as a cow, monkey, horse,sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit orguinea pig, in one embodiment a mammal, in another embodiment a human.In one embodiment, a “patient” or “subject” is a human having advancednon-small cell lung cancer. In one embodiment, a “patient” or “subject”is a human having Stage IIIB/IV non-small cell lung cancer. In oneembodiment, a “patient” or “subject” is a human having advancednon-small cell lung cancer. In one embodiment, a “patient” or “subject”is a human having Stage IIIB/IV non-small cell lung cancer who hasfailed at least one line of standard therapy. In one embodiment, apatient is a human having histologically or cytologically-confirmedadvanced non-small cell lung cancer, including subjects who haveprogressed on (or not been able to tolerate) standard anticancer therapyor for whom no standard anticancer therapy exists. In one embodiment,the standard anticancer therapy is chemotherapy or EGFR inhibitortherapy,

In the context of advanced non-small cell lung cancer, inhibition may beassessed by inhibition of disease progression, inhibition of tumorgrowth, reduction of primary tumor, relief of tumor-related symptoms,inhibition of tumor secreted factors (including tumor secreted hormones,such as those that contribute to carcinoid syndrome), delayed appearanceof primary or secondary tumors, slowed development of primary orsecondary tumors, decreased occurrence of primary or secondary tumors,slowed or decreased severity of secondary effects of disease, arrestedtumor growth and regression of tumors, increased Time To Progression(TTP), increased Progression Free Survival (PFS), increased OverallSurvival (OS), among others. OS as used herein means the time fromrandomization until death from any cause, and is measured in theintent-to-treat population. TTP as used herein means the time fromrandomization until objective tumor progression; TTP does not includedeaths. As used herein, PFS means the time from randomization untilobjective tumor progression or death. In one embodiment, PFS rates willbe computed using the Kaplan-Meier estimates. In the extreme, completeinhibition, is referred to herein as prevention or chemoprevention. Inthis context, the term “prevention” includes either preventing the onsetof clinically evident advanced non-small cell lung cancer altogether orpreventing the onset of a preclinically evident stage of advancednon-small cell lung cancer. Also intended to be encompassed by thisdefinition is the prevention of transformation into malignant cells orto arrest or reverse the progression of premalignant cells to malignantcells. This includes prophylactic treatment of those at risk ofdeveloping advanced non-small cell lung cancer. In certain embodiments,the advanced non-small cell lung cancer can be Stage IIIB or Stage IVnon-small cell lung cancer.

In certain embodiments, the treatment of non-small cell lung cancer maybe assessed by Response Evaluation Criteria in Solid Tumors (RECIST 1.1)(see Thereasse P., et al. New Guidelines to Evaluate the Response toTreatment in Solid Tumors. J. of the National Cancer Institute; 2000;(92) 205-216 and Eisenhauer E. A., Therasse P., Bogaerts J., et al. Newresponse evaluation criteria in solid tumours: Revised RECIST guideline(version 1.1). European J. Cancer; 2009; (45) 228-247). Overallresponses for all possible combinations of tumor responses in target andnon-target lesions with our without the appearance of new lesions are asfollows:

Target lesions Non-target lesions New lesions Overall response CR CR NoCR CR Incomplete No PR response/SD PR Non-PD No PR SD Non-PD No SD PDAny Yes or no PD Any PD Yes or no PD Any Any Yes PD CR = completeresponse; PR = partial response; SD = stable disease; and PD =progressive disease.

With respect to the evaluation of target lesions, complete response (CR)is the disappearance of all target lesions, partial response (PR) is atleast a 30% decrease in the sum of the longest diameter of targetlesions, taking as reference the baseline sum longest diameter,progressive disease (PD) is at least a 20% increase in the sum of thelongest diameter of target lesions, taking as reference the smallest sumlongest diameter recorded since the treatment started or the appearanceof one or more new lesions and stable disease (SD) is neither sufficientshrinkage to qualify for partial response nor sufficient increase toqualify for progressive disease, taking as reference the smallest sumlongest diameter since the treatment started.

With respect to the evaluation of non-target lesions, complete response(CR) is the disappearance of all non-target lesions and normalization oftumor marker level; incomplete response/stable disease (SD) is thepersistence of one or more non-target lesion(s) and/or the maintenanceof tumor marker level above the normal limits, and progressive disease(PD) is the appearance of one or more new lesions and/or unequivocalprogression of existing non-target lesions.

In certain embodiments, treatment of non-small cell lung cancer may beassessed by the inhibition of phosphorylation of S6RP, 4E-BPI and/or AKTin circulating blood and/or tumor cells, or tumor biopsies/aspirates,before, during and/or after treatment with a TOR kinase inhibitor. Forexample, the inhibition of phosphorylation of S6RP, 4E-BPI and/or AKT isassessed in B-cells, T-cells and/or monocytes.

5.2 TOR Kinase Inhibitors

The compounds provided herein are generally referred to as “TOR kinaseinhibitor(s).” In a specific embodiment, the TOR kinase inhibitors donot include rapamycin or rapamycin analogs (rapalogs).

In one embodiment, the TOR kinase inhibitors include compounds havingthe following formula (I):

and pharmaceutically acceptable salts, clathrates, solvates,stereoisomers, tautomers, and prodrugs thereof, wherein:

X, Y and Z are at each occurrence independently N or CR³, wherein atleast one of X, Y and Z is N and at least one of X, Y and Z is CR³;

-A-B-Q- taken together form —CHR⁴C(O)NH—, —C(O)CHR⁴NH—, —C(O)NH—,—CH₂C(O)O—, —C(O)CH₂O—, —C(O)O— or C(O)NR³;

L is a direct bond, NH or O;

R¹ is H, substituted or unsubstituted C₁₋₈alkyl, substituted orunsubstituted C₂₋₈alkenyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedcycloalkyl or substituted or unsubstituted heterocyclylalkyl;

R² is H, substituted or unsubstituted C₁₋₈alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl;

R³ is H, substituted or unsubstituted C₁₋₈alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, substituted or unsubstitutedheterocyclylalkyl, —NHR⁴ or —N(R⁴)₂; and

R⁴ is at each occurrence independently substituted or unsubstitutedC₁₋₈alkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, orsubstituted or unsubstituted heterocyclylalkyl.

In one embodiment, the TOR kinase inhibitors of formula (I) are thosewherein -A-B-Q- taken together form —CH₂C(O)NH—.

In another embodiment, the TOR kinase inhibitors of formula (I) arethose wherein -A-B-Q- taken together form —C(O)CH₂NH—.

In another embodiment, the TOR kinase inhibitors of formula (I) arethose wherein -A-B-Q- taken together form —C(O)NH—.

In another embodiment, the TOR kinase inhibitors of formula (I) arethose wherein -A-B-Q- taken together form —CH₂C(O)O—.

In another embodiment, the TOR kinase inhibitors of formula (I) arethose wherein -A-B-Q- taken together form —C(O)CH₂O—.

In another embodiment, the TOR kinase inhibitors of formula (I) arethose wherein -A-B-Q- taken together form —C(O)O—.

In another embodiment, the TOR kinase inhibitors of formula (I) arethose wherein -A-B-Q- taken together form —C(O)NR³—.

In another embodiment, the TOR kinase inhibitors of formula (I) arethose wherein Y is CR³.

In another embodiment, the TOR kinase inhibitors of formula (I) arethose wherein X and Z are N and Y is CR³.

In another embodiment, the TOR kinase inhibitors of formula (I) arethose wherein X and Z are N and Y is CH.

In another embodiment, the TOR kinase inhibitors of formula (I) arethose wherein X and Z are CH and Y is N.

In another embodiment, the TOR kinase inhibitors of formula (I) arethose wherein Y and Z are CH and X is N.

In another embodiment, the TOR kinase inhibitors of formula (I) arethose wherein X and Y are CH and Z is N.

In another embodiment, the TOR kinase inhibitors of formula (I) arethose wherein R¹ is substituted aryl, such as substituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (I) arethose wherein R¹ is substituted or unsubstituted aryl, such assubstituted or unsubstituted phenyl or substituted or unsubstitutednaphthyl.

In another embodiment, the TOR kinase inhibitors of formula (I) arethose wherein R¹ is substituted or unsubstituted heteroaryl, such assubstituted or unsubstituted quinoline, substituted or unsubstitutedpyridine, substituted or unsubstituted pyrimidine, substituted orunsubstituted indole, or substituted or unsubstituted thiophene.

In another embodiment, the TOR kinase inhibitors of formula (I) arethose wherein R¹ is H.

In another embodiment, the TOR kinase inhibitors of formula (I) arethose wherein R² is substituted C₁₋₈alkyl.

In another embodiment, the TOR kinase inhibitors of formula (I) arethose wherein R² is methyl or ethyl substituted with substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl.

In another embodiment, the TOR kinase inhibitors of formula (I) arethose wherein R² is substituted or unsubstituted cycloalkyl orsubstituted or unsubstituted heterocyclylalkyl.

In another embodiment, the TOR kinase inhibitors of formula (I) arethose wherein R² is substituted or unsubstituted aryl, such assubstituted or unsubstituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (I) arethose wherein R² is H.

In another embodiment, the TOR kinase inhibitors of formula (I) arethose wherein L is a direct bond.

In another embodiment, the TOR kinase inhibitors of formula (I) arethose wherein -A-B-Q- taken together form —C(O)NH—, X and Z are N and Yis CH, R¹ is substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl, L is a direct bond, and R² is substituted orunsubstituted C₁₋₈alkyl.

In another embodiment, the TOR kinase inhibitors of formula (I) arethose wherein -A-B-Q- taken together form —C(O)NH—, X and Z are N and Yis CH, R¹ is substituted or unsubstituted aryl, L is a direct bond, andR² is substituted or unsubstituted C₁₋₈alkyl.

In another embodiment, the TOR kinase inhibitors of formula (I) arethose wherein -A-B-Q- taken together form —C(O)NH—, X and Z are N and Yis CH, R¹ is substituted or unsubstituted aryl, and R² is C₁₋₈alkylsubstituted with one or more substituents selected from alkoxy, amino,hydroxy, cycloalkyl, or heterocyclylalkyl.

In another embodiment, the TOR kinase inhibitors of formula (I) arethose wherein -A-B-Q- taken together form —C(O)NH—, X and Z are N and Yis CH, R¹ is substituted or unsubstituted aryl, and R² is substituted orunsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl.

In another embodiment, the TOR kinase inhibitors of formula (I) arethose wherein -A-B-Q- taken together form —C(O)NH—, X and Z are N and Yis CH, R¹ is substituted phenyl, L is a direct bond, and R² issubstituted C₁₋₈alkyl.

In another embodiment, the TOR kinase inhibitors of formula (I) do notinclude compounds wherein X and Z are both N and Y is CH, -A-B-Q- is—C(O)NH—, L is a direct bond, R¹ is substituted or unsubstituted aryl orsubstituted or unsubstituted heteroaryl, and R² is C₁₋₈alkyl substitutedwith substituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl.

In another embodiment, the TOR kinase inhibitors of formula (I) do notinclude compounds wherein X and Z are both N and Y is CH, -A-B-Q- is—C(O)NH—, L is a direct bond, R¹ is phenyl, naphthyl, indanyl orbiphenyl, each of which may be optionally substituted with one or moresubstituents independently selected from the group consistingsubstituted or unsubstituted C₁₋₈alkyl, substituted or unsubstitutedC₂₋₈alkenyl, substituted or unsubstituted aryl, substituted orunsubstituted cycloalkyl or substituted or unsubstitutedheterocyclylalkyl.

In another embodiment, the TOR kinase inhibitors of formula (I) do notinclude compounds wherein X and Z are both N and Y is CH, -A-B-Q- is—C(O)NH—, L is a direct bond, R¹ is phenyl, naphthyl or biphenyl, eachof which may be optionally substituted with one or more substituentseach independently selected from the group consisting of C₁₋₄alkyl,amino, aminoC₁₋₁₂alkyl, halogen, hydroxy, hydroxyC₁₋₄alkyl, —CF₃,aryloxy, arylC₁₋₁₂alkoxy, —CN, —COR_(g), —COOR_(g), —CONR_(g)R_(h),—NR_(g)COR_(h), —SO₂R_(g), —SO₃R_(g) or —SO₂NR_(g)R_(h), wherein eachR_(g) and R_(h) are independently selected from the group consisting ofhydrogen, C₁₋₄alkyl, C₃₋₆cycloalkyl, aryl, arylC₁₋₆alkyl, heteroaryl orheteroarylC₁₋₆alkyl; or A is a 5- to 6-membered monocyclicheteroaromatic ring having from one, two, three or four heteroatomsindependently selected from the group consisting of N, O and S, thatmonocyclic heteroaromatic ring may be optionally substituted with one ormore substituents each independently selected from the group consistingof C₁₋₆alkyl, amino, aminoC₁₋₁₂alkyl, halogen, hydroxy,hydroxyC₁₋₄alkyl, C₁₋₄alkyloxyC₁₋₄alkyl, C₁₋₁₂alkoxy, aryloxy, arylC₁₋₁₂alkoxy, —CN, —CF₃, —OCF₃, —COR_(i), —COOR_(i), —CONR_(i)R_(j),—NR_(i)COR_(j), —NR_(i)SO₂R_(j), —SO₂R_(i), —SO₃R_(i), or—SO₂NR_(i)R_(j), wherein each R_(i) and R_(j) are independently selectedfrom the group consisting of hydrogen, C₁₋₄ alkyl, C₃₋₆cycloalkyl, aryl,arylC₁₋₆alkyl, heteroaryl or heteroarylC₁₋₆alkyl; or A is a 8- to 10membered bicyclic heteroaromatic ring from one, two, three or fourheteroatoms selected from the group consisting of N, O and S, and may beoptionally substituted with one, two or three substituents eachindependently selected from the group consisting of C₁₋₆alkyl, amino,aminoC₁₋₁₂alkyl, halogen, hydroxy, hydroxyC₁₋₄alkyl,C₁₋₄alkyloxyC₁₋₄alkyl, aryloxy, aryl C₁₋₁₂alkoxy, —CN, —CF₃, —OCF₃,—COR_(k), —COOR_(k), —CONR_(k)R_(l), —NR_(k)COR_(l), —NR_(k)SO₂R_(l),—SO₂R_(k), —SO₃R_(k) or —SO₂NR_(k)R_(l), wherein each R_(k) and R_(l)are independently selected from the group consisting of hydrogen, C₁₋₄alkyl, C₃₋₆ cycloalkyl, aryl, arylC₁₋₆alkyl, heteroaryl orheteroarylC₁₋₆alkyl, and R² is C₁₋₈alkyl substituted with substituted orunsubstituted aryl or substituted or unsubstituted heteroaryl.

In another embodiment, the TOR kinase inhibitors of formula (I) do notinclude compounds wherein X and Y are both N and Z is CH, -A-B-Q- is—C(O)NH—, L is a direct bond, R¹ is substituted or unsubstituted phenylor substituted or unsubstituted heteroaryl, and R² is substituted orunsubstituted methyl, unsubstituted ethyl, unsubstituted propyl, or anacetamide.

In another embodiment, the TOR kinase inhibitors of formula (I) do notinclude compounds wherein X and Y are both N and Z is CH, -A-B-Q- is—C(O)NH—, L is a direct bond, R¹ is substituted or unsubstituted phenylor substituted or unsubstituted heteroaryl, and R² is an acetamide.

In another embodiment, the TOR kinase inhibitors of formula (I) do notinclude compounds wherein X is N and Y and Z are both CH, -A-B-Q- is—C(O)NH—, L is a direct bond, R¹ is a(2,5′-Bi-1H-benzimidazole)-5-carboxamide, and R² is H.

In another embodiment, the TOR kinase inhibitors of formula (I) do notinclude compounds wherein one of X and Z is CH and the other is N, Y isCH, -A-B-Q- is —C(O)NH—, L is a direct bond, R¹ is unsubstitutedpyridine, and R² is H, methyl or substituted ethyl.

In another embodiment, the TOR kinase inhibitors of formula (I) do notinclude compounds wherein X and Z are both N and Y is CH, -A-B-Q- is—C(O)NH—, R¹ is H, C₁₋₈alkyl, C₂₋₈alkenyl, aryl or cycloalkyl, and L isNH.

In another embodiment, the TOR kinase inhibitors of formula (I) do notinclude compounds wherein X and Z are both N and Y is CH, -A-B-Q- is—C(O)NR³—, R² is H, substituted or unsubstituted C₁₋₈alkyl, substitutedor unsubstituted phenyl, substituted or unsubstituted cycloalkyl, orsubstituted or unsubstituted heterocyclylalkyl, and L is NH.

In another embodiment, the TOR kinase inhibitors of formula (I) do notinclude compounds wherein R¹ is a substituted or unsubstitutedoxazolidinone.

In another embodiment, the TOR kinase inhibitors of formula (I) do notinclude one or more of the following compounds:1,7-dihydro-2-phenyl-8H-Purin-8-one,1,2-dihydro-3-phenyl-6H-Imidazo[4,5-e]-1,2,4-triazin-6-one,1,3-dihydro-6-(4-pyridinyl)-2H-Imidazo[4,5-b]pyridin-2-one,6-(1,3-benzodioxol-5-yl)-1,3-dihydro-1-[(1S)-1-phenylethyl]-2H-Imidazo[4,5-b]pyrazin-2-one,3-[2,3-dihydro-2-oxo-3-(4-pyridinylmethyl)-1H-imidazo[4,5-b]pyrazin-5-yl]-Benzamide,1-[2-(dimethylamino)ethyl]-1,3-dihydro-6-(3,4,5-trimethoxyphenyl)-2H-Imidazo[4,5-b]pyrazin-2-one,N-[5-(1,1-dimethylethyl)-2-methoxyphenyl]-N′-[4-(1,2,3,4-tetrahydro-2-oxopyrido[2,3-b]pyrazin-7-yl)-1-naphthalenyl]-Urea,N-[4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-6-yl)-1-naphthalenyl]-N′-[5-(1,1-dimethylethyl)-2-methoxyphenyl]-Urea,1,3-dihydro-5-phenyl-2H-Imidazo[4,5-b]pyrazin-2-one,1,3-dihydro-5-phenoxy-2H-Imidazo[4,5-b]pyridin-2-one,1,3-dihydro-1-methyl-6-phenyl-2H-Imidazo[4,5-b]pyridin-2-one,1,3-dihydro-5-(1H-imidazol-1-yl) 2H-Imidazo[4,5-b]pyridin-2-one,6-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-6-yl)-8-methyl-2(1H)-Quinolinoneand 7,8-dihydro-8-oxo-2-phenyl-9H-purine-9-acetic acid.

In one embodiment, the TOR kinase inhibitors include compounds havingthe following formula (Ia):

and pharmaceutically acceptable salts, clathrates, solvates,stereoisomers, tautomers, and prodrugs thereof, wherein:

L is a direct bond, NH or O;

Y is N or CR³;

R¹ is H, substituted or unsubstituted C₁₋₈alkyl, substituted orunsubstituted C₂₋₈alkenyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedcycloalkyl or substituted or unsubstituted heterocyclylalkyl;

R² is H, substituted or unsubstituted C₁₋₈alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl;

R³ is H, substituted or unsubstituted C₁₋₈alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, substituted or unsubstitutedheterocyclylalkyl, —NHR⁴ or —N(R⁴)₂; and

R⁴ is at each occurrence independently substituted or unsubstitutedC₁₋₈alkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, orsubstituted or unsubstituted heterocyclylalkyl.

In one embodiment, the TOR kinase inhibitors of formula (Ia) are thosewherein R¹ is substituted aryl, such as substituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (Ia) arethose wherein R¹ is substituted or unsubstituted aryl, such assubstituted or unsubstituted phenyl or substituted or unsubstitutednaphthyl.

In another embodiment, the TOR kinase inhibitors of formula (Ia) arethose wherein R¹ is substituted or unsubstituted heteroaryl, such assubstituted or unsubstituted quinoline, substituted or unsubstitutedpyridine, substituted or unsubstituted pyrimidine, substituted orunsubstituted indole, or substituted or unsubstituted thiophene.

In another embodiment, the TOR kinase inhibitors of formula (Ia) arethose wherein R¹ is H.

In another embodiment, the TOR kinase inhibitors of formula (Ia) arethose wherein R² is substituted C₁₋₈alkyl.

In another embodiment, the TOR kinase inhibitors of formula (Ia) arethose wherein R² is methyl or ethyl substituted with substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl.

In another embodiment, the TOR kinase inhibitors of formula (Ia) arethose wherein R² is substituted or unsubstituted cycloalkyl orsubstituted or unsubstituted heterocyclylalkyl.

In another embodiment, the TOR kinase inhibitors of formula (Ia) arethose wherein R² is substituted or unsubstituted aryl, such assubstituted or unsubstituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (Ia) arethose wherein R² is H.

In another embodiment, the TOR kinase inhibitors of formula (Ia) arethose wherein Y is CH.

In another embodiment, the TOR kinase inhibitors of formula (Ia) arethose wherein L is a direct bond.

In another embodiment, the TOR kinase inhibitors of formula (Ia) arethose wherein R¹ is substituted or unsubstituted aryl and R² isunsubstituted C₁₋₈alkyl.

In another embodiment, the TOR kinase inhibitors of formula (Ia) arethose wherein R¹ is substituted or unsubstituted aryl and R² isC₁₋₈alkyl substituted with one or more substituents selected fromalkoxy, amino, hydroxy, cycloalkyl, or heterocyclylalkyl.

In another embodiment, the TOR kinase inhibitors of formula (Ia) arethose wherein R¹ is substituted or unsubstituted aryl and R² issubstituted or unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl.

In another embodiment, the TOR kinase inhibitors of formula (Ia) do notinclude compounds wherein Y is CH, L is a direct bond, R¹ is substitutedor unsubstituted aryl or substituted or unsubstituted heteroaryl, and R²is C₁₋₈alkyl substituted with substituted or unsubstituted aryl orsubstituted or unsubstituted heteroaryl.

In one embodiment, the TOR kinase inhibitors include compounds havingthe following formula (Ib):

and pharmaceutically acceptable salts, clathrates, solvates,stereoisomers, tautomers, and prodrugs thereof, wherein:

L is a direct bond, NH or O;

R¹ is H, substituted or unsubstituted C₁₋₈alkyl, substituted orunsubstituted C₂₋₈alkenyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedcycloalkyl or substituted or unsubstituted heterocyclylalkyl; and

R² is H, substituted or unsubstituted C₁₋₈alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl.

In one embodiment, the TOR kinase inhibitors of formula (Ib) are thosewherein R¹ is substituted aryl, such as substituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (Ib) arethose wherein R¹ is substituted or unsubstituted aryl, such assubstituted or unsubstituted phenyl or substituted or unsubstitutednaphthyl.

In another embodiment, the TOR kinase inhibitors of formula (Ib) arethose wherein R¹ is substituted or unsubstituted heteroaryl, such assubstituted or unsubstituted quinoline, substituted or unsubstitutedpyridine, substituted or unsubstituted pyrimidine, substituted orunsubstituted indole, or substituted or unsubstituted thiophene.

In another embodiment, the TOR kinase inhibitors of formula (Ib) arethose wherein R¹ is H.

In another embodiment, the TOR kinase inhibitors of formula (Ib) arethose wherein R² is substituted C₁₋₈alkyl.

In another embodiment, the TOR kinase inhibitors of formula (Ib) arethose wherein R² is methyl or ethyl substituted with substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl.

In another embodiment, the TOR kinase inhibitors of formula (Ib) arethose wherein R² is substituted or unsubstituted cycloalkyl orsubstituted or unsubstituted heterocyclylalkyl.

In another embodiment, the TOR kinase inhibitors of formula (Ib) arethose wherein R² is substituted or unsubstituted aryl, such assubstituted or unsubstituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (Ib) arethose wherein R² is H.

In another embodiment, the TOR kinase inhibitors of formula (Ib) arethose wherein L is a direct bond.

In another embodiment, the TOR kinase inhibitors of formula (Ib) arethose wherein R¹ is substituted or unsubstituted aryl and R² isunsubstituted C₁₋₈alkyl.

In another embodiment, the TOR kinase inhibitors of formula (Ib) arethose wherein R¹ is substituted or unsubstituted aryl and R² isC₁₋₈alkyl substituted with one or more substituents selected fromalkoxy, amino, hydroxy, cycloalkyl, or heterocyclylalkyl.

In another embodiment, the TOR kinase inhibitors of formula (Ib) arethose wherein R¹ is substituted or unsubstituted aryl and R² issubstituted or unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl.

In one embodiment, the TOR kinase inhibitors include compounds havingthe following formula (Ic):

and pharmaceutically acceptable salts, clathrates, solvates,stereoisomers, tautomers, and prodrugs thereof, wherein:

L is a direct bond, NH or O;

R¹ is H, substituted or unsubstituted C₁₋₈alkyl, substituted orunsubstituted C₂₋₈alkenyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedcycloalkyl or substituted or unsubstituted heterocyclylalkyl; and

R² is H, substituted or unsubstituted C₁₋₈alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl.

In one embodiment, the TOR kinase inhibitors of formula (Ic) are thosewherein R¹ is substituted aryl, such as substituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (Ic) arethose wherein R¹ is substituted or unsubstituted aryl, such assubstituted or unsubstituted phenyl or substituted or unsubstitutednaphthyl.

In another embodiment, the TOR kinase inhibitors of formula (Ic) arethose wherein R¹ is substituted or unsubstituted heteroaryl, such assubstituted or unsubstituted quinoline, substituted or unsubstitutedpyridine, substituted or unsubstituted pyrimidine, substituted orunsubstituted indole, or substituted or unsubstituted thiophene.

In another embodiment, the TOR kinase inhibitors of formula (Ic) arethose wherein R¹ is H.

In another embodiment, the TOR kinase inhibitors of formula (Ic) arethose wherein R² is substituted C₁₋₈alkyl.

In another embodiment, the TOR kinase inhibitors of formula (Ic) arethose wherein R² is methyl or ethyl substituted with substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl.

In another embodiment, the TOR kinase inhibitors of formula (Ic) arethose wherein R² is substituted or unsubstituted cycloalkyl orsubstituted or unsubstituted heterocyclylalkyl.

In another embodiment, the TOR kinase inhibitors of formula (Ic) arethose wherein R² is substituted or unsubstituted aryl, such assubstituted or unsubstituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (Ic) arethose wherein R² is H.

In another embodiment, the TOR kinase inhibitors of formula (Ic) arethose wherein L is a direct bond.

In another embodiment, the TOR kinase inhibitors of formula (Ic) arethose wherein R¹ is substituted or unsubstituted aryl and R² isunsubstituted C₁₋₈alkyl.

In another embodiment, the TOR kinase inhibitors of formula (Ic) arethose wherein R¹ is substituted or unsubstituted aryl and R² isC₁₋₈alkyl substituted with one or more substituents selected fromalkoxy, amino, hydroxy, cycloalkyl, or heterocyclylalkyl.

In another embodiment, the TOR kinase inhibitors of formula (Ic) arethose wherein R¹ is substituted or unsubstituted aryl and R² issubstituted or unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl.

In one embodiment, the TOR kinase inhibitors include compounds havingthe following formula (Id):

and pharmaceutically acceptable salts, clathrates, solvates,stereoisomers, tautomers, and prodrugs thereof, wherein:

L is a direct bond, NH or O;

R¹ is H, substituted or unsubstituted C₁₋₈alkyl, substituted orunsubstituted C₂₋₈alkenyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedcycloalkyl or substituted or unsubstituted heterocyclylalkyl; and

R² is H, substituted or unsubstituted C₁₋₈alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl.

In one embodiment, the TOR kinase inhibitors of formula (Id) are thosewherein R¹ is substituted aryl, such as substituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (Id) arethose wherein R¹ is substituted or unsubstituted aryl, such assubstituted or unsubstituted phenyl or substituted or unsubstitutednaphthyl.

In another embodiment, the TOR kinase inhibitors of formula (Id) arethose wherein R¹ is substituted or unsubstituted heteroaryl, such assubstituted or unsubstituted quinoline, substituted or unsubstitutedpyridine, substituted or unsubstituted pyrimidine, substituted orunsubstituted indole, or substituted or unsubstituted thiophene.

In another embodiment, the TOR kinase inhibitors of formula (Id) arethose wherein R¹ is H.

In another embodiment, the TOR kinase inhibitors of formula (Id) arethose wherein R² is substituted C₁₋₈alkyl.

In another embodiment, the TOR kinase inhibitors of formula (Id) arethose wherein R² is methyl or ethyl substituted with substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl.

In another embodiment, the TOR kinase inhibitors of formula (Id) arethose wherein R² is substituted or unsubstituted cycloalkyl orsubstituted or unsubstituted heterocyclylalkyl.

In another embodiment, the TOR kinase inhibitors of formula (Id) arethose wherein R² is substituted or unsubstituted aryl, such assubstituted or unsubstituted phenyl.

In another embodiment, the Heteroaryl Compounds of formula (Id) arethose wherein R² is H.

In another embodiment, the TOR kinase inhibitors of formula (Id) arethose wherein L is a direct bond.

In another embodiment, the TOR kinase inhibitors of formula (Id) arethose wherein R¹ is substituted or unsubstituted aryl and R² isunsubstituted C₁₋₈alkyl.

In another embodiment, the TOR kinase inhibitors of formula (Id) arethose wherein R¹ is substituted or unsubstituted aryl and R² isC₁₋₈alkyl substituted with one or more substituents selected fromalkoxy, amino, hydroxy, cycloalkyl, or heterocyclylalkyl.

In another embodiment, the TOR kinase inhibitors of formula (Id) arethose wherein R¹ is substituted or unsubstituted aryl and R² issubstituted or unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl.

In one embodiment, the TOR kinase inhibitors include compounds havingthe following formula (Ie):

and pharmaceutically acceptable salts, clathrates, solvates,stereoisomers, tautomers, and prodrugs thereof, wherein:

L is a direct bond, NH or O;

R¹ is H, substituted or unsubstituted C₁₋₈alkyl, substituted orunsubstituted C₂₋₈alkenyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedcycloalkyl or substituted or unsubstituted heterocyclylalkyl; and

R² is H, substituted or unsubstituted C₁₋₈alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl.

In one embodiment, the TOR kinase inhibitors of formula (Ie) are thosewherein R¹ is substituted aryl, such as substituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (Ie) arethose wherein R¹ is substituted or unsubstituted aryl, such assubstituted or unsubstituted phenyl or substituted or unsubstitutednaphthyl.

In another embodiment, the TOR kinase inhibitors of formula (Ie) arethose wherein R¹ is substituted or unsubstituted heteroaryl, such assubstituted or unsubstituted quinoline, substituted or unsubstitutedpyridine, substituted or unsubstituted pyrimidine, substituted orunsubstituted indole, or substituted or unsubstituted thiophene.

In another embodiment, the TOR kinase inhibitors of formula (Ie) arethose wherein R¹ is H.

In another embodiment, the TOR kinase inhibitors of formula (Ie) arethose wherein R² is substituted C₁₋₈alkyl.

In another embodiment, the TOR kinase inhibitors of formula (Ie) arethose wherein R² is methyl or ethyl substituted with substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl.

In another embodiment, the TOR kinase inhibitors of formula (Ie) arethose wherein R² is substituted or unsubstituted cycloalkyl orsubstituted or unsubstituted heterocyclylalkyl.

In another embodiment, the TOR kinase inhibitors of formula (Ie) arethose wherein R² is substituted or unsubstituted aryl, such assubstituted or unsubstituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (Ie) arethose wherein R² is H.

In another embodiment, the TOR kinase inhibitors of formula (Ie) arethose wherein L is a direct bond.

In another embodiment, the TOR kinase inhibitors of formula (Ie) arethose wherein R¹ is substituted or unsubstituted aryl and R² isunsubstituted C₁₋₈alkyl.

In another embodiment, the TOR kinase inhibitors of formula (Ie) arethose wherein R¹ is substituted or unsubstituted aryl and R² isC₁₋₈alkyl substituted with one or more substituents selected fromalkoxy, amino, hydroxy, cycloalkyl, or heterocyclylalkyl.

In another embodiment, the TOR kinase inhibitors of formula (Ie) arethose wherein R¹ is substituted or unsubstituted aryl and R² issubstituted or unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl.

In one embodiment, the TOR kinase inhibitors include compounds havingthe following formula (If):

and pharmaceutically acceptable salts, clathrates, solvates,stereoisomers, tautomers, and prodrugs thereof, wherein:

L is a direct bond, NH or O;

R¹ is H, substituted or unsubstituted C₁₋₈alkyl, substituted orunsubstituted C₂₋₈alkenyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedcycloalkyl or substituted or unsubstituted heterocyclylalkyl; and

R² is H, substituted or unsubstituted C₁₋₈alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl.

In one embodiment, the TOR kinase inhibitors of formula (If) are thosewherein R¹ is substituted aryl, such as substituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (If) arethose wherein R¹ is substituted or unsubstituted aryl, such assubstituted or unsubstituted phenyl or substituted or unsubstitutednaphthyl.

In another embodiment, the TOR kinase inhibitors of formula (If) arethose wherein R¹ is substituted or unsubstituted heteroaryl, such assubstituted or unsubstituted quinoline, substituted or unsubstitutedpyridine, substituted or unsubstituted pyrimidine, substituted orunsubstituted indole, or substituted or unsubstituted thiophene.

In another embodiment, the TOR kinase inhibitors of formula (If) arethose wherein R¹ is H.

In another embodiment, the TOR kinase inhibitors of formula (If) arethose wherein R² is substituted C₁₋₈alkyl.

In another embodiment, the TOR kinase inhibitors of formula (If) arethose wherein R² is methyl or ethyl substituted with substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl.

In another embodiment, the TOR kinase inhibitors of formula (If) arethose wherein R² is substituted or unsubstituted cycloalkyl orsubstituted or unsubstituted heterocyclylalkyl.

In another embodiment, the TOR kinase inhibitors of formula (If) arethose wherein R² is substituted or unsubstituted aryl, such assubstituted or unsubstituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (If) arethose wherein R² is H.

In another embodiment, the TOR kinase inhibitors of formula (If) arethose wherein L is a direct bond.

In another embodiment, the TOR kinase inhibitors of formula (If) arethose wherein R¹ is substituted or unsubstituted aryl and R² isunsubstituted C₁₋₈alkyl.

In another embodiment, the TOR kinase inhibitors of formula (If) arethose wherein R¹ is substituted or unsubstituted aryl and R² isC₁₋₈alkyl substituted with one or more substituents selected fromalkoxy, amino, hydroxy, cycloalkyl, or heterocyclylalkyl.

In another embodiment, the TOR kinase inhibitors of formula (If) arethose wherein R¹ is substituted or unsubstituted aryl and R² issubstituted or unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl.

In one embodiment, the TOR kinase inhibitors include compounds havingthe following formula (Ig):

and pharmaceutically acceptable salts, clathrates, solvates,stereoisomers, tautomers, and prodrugs thereof, wherein:

L is a direct bond, NH or O;

R¹ is H, substituted or unsubstituted C₁₋₈alkyl, substituted orunsubstituted C₂₋₈alkenyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedcycloalkyl or substituted or unsubstituted heterocyclylalkyl; and

R² is H, substituted or unsubstituted C₁₋₈alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl.

In one embodiment, the TOR kinase inhibitors of formula (Ig) are thosewherein R¹ is substituted aryl, such as substituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (Ig) arethose wherein R¹ is substituted or unsubstituted aryl, such assubstituted or unsubstituted phenyl or substituted or unsubstitutednaphthyl.

In another embodiment, the TOR kinase inhibitors of formula (Ig) arethose wherein R¹ is substituted or unsubstituted heteroaryl, such assubstituted or unsubstituted quinoline, substituted or unsubstitutedpyridine, substituted or unsubstituted pyrimidine, substituted orunsubstituted indole, or substituted or unsubstituted thiophene.

In another embodiment, the TOR kinase inhibitors of formula (Ig) arethose wherein R¹ is H.

In another embodiment, the TOR kinase inhibitors of formula (Ig) arethose wherein R² is substituted C₁₋₈alkyl.

In another embodiment, the TOR kinase inhibitors of formula (Ig) arethose wherein R² is methyl or ethyl substituted with substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl.

In another embodiment, the TOR kinase inhibitors of formula (Ig) arethose wherein R² is substituted or unsubstituted cycloalkyl orsubstituted or unsubstituted heterocyclylalkyl.

In another embodiment, the TOR kinase inhibitors of formula (Ig) arethose wherein R² is substituted or unsubstituted aryl, such assubstituted or unsubstituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (Ig) arethose wherein R² is H.

In another embodiment, the TOR kinase inhibitors of formula (Ig) arethose wherein L is a direct bond.

In another embodiment, the TOR kinase inhibitors of formula (Ig) arethose wherein R¹ is substituted or unsubstituted aryl and R² isunsubstituted C₁₋₈alkyl.

In another embodiment, the TOR kinase inhibitors of formula (Ig) arethose wherein R¹ is substituted or unsubstituted aryl and R² isC₁₋₈alkyl substituted with one or more substituents selected fromalkoxy, amino, hydroxy, cycloalkyl, or heterocyclylalkyl.

In another embodiment, the TOR kinase inhibitors of formula (Ig) arethose wherein R¹ is substituted or unsubstituted aryl and R² issubstituted or unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl.

Representative TOR kinase inhibitors of formula (I) include compoundsfrom Table A.

TABLE A(S)-1-(1-hydroxy-3-methylbutan-2-yl)-6-phenyl-1H-imidazo[4,5-b]pyrazin-2(3H)-one;1-((tetrahydro-2H-pyran-4-yl)methyl)-6-(3,4,5-trimethoxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;(R)-6-(naphthalen-1-yl)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;1-(3-methoxybenzyl)-6-(4-(methylsulfonyl)phenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;(S)-1-(1-phenylethyl)-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(4-hydroxyphenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;(S)-6-(naphthalen-1-yl)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;(S)-1-(1-hydroxy-3-methylbutan-2-yl)-6-(5-isopropyl-2-methoxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;(R)-1-(1-hydroxy-3-methylbutan-2-yl)-6-phenyl-1H-imidazo[4,5-b]pyrazin-2(3H)-one;(R)-1-(1-phenylethyl)-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;(S)-1-(1-hydroxy-3-methylbutan-2-yl)-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;(R)-1-(1-hydroxy-3-methylbutan-2-yl)-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;(R)-1-(1-hydroxy-3-methylbutan-2-yl)-6-(5-isopropyl-2-methoxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;1-benzyl-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;1-(4-methoxybenzyl)-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;(R)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;(S)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;1-isopropyl-6-(5-isopropyl-2-methoxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;1-cyclohexyl-6-(5-isopropyl-2-methoxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;5-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;1-isobutyl-6-(5-isopropyl-2-methoxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;1-(2-hydroxyethyl)-6-(5-isopropyl-2-methoxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(5-isopropyl-2-methoxyphenyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;(R)-1-(1-phenylethyl)-6-(quinolin-5-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one;(S)-1-(1-phenylethyl)-6-(quinolin-5-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one;3-(1-phenylethyl)-5-(quinolin-5-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one;(R)-3-(1-phenylethyl)-5-(quinolin-5-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one;(R)-6-(5-isopropyl-2-methoxyphenyl)-1-(3-methylbutan-2-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;(S)-6-(5-isopropyl-2-methoxyphenyl)-1-(tetrahydrofuran-3-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;(S)-6-(5-isopropyl-2-methoxyphenyl)-1-(3-methylbutan-2-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;1-cyclopentyl-6-(5-isopropyl-2-methoxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;(R)-6-(5-isopropyl-2-methoxyphenyl)-1-(tetrahydrofuran-3-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;1-(cyclopropylmethyl)-6-(5-isopropyl-2-methoxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;1-(cyclopentylmethyl)-6-(5-isopropyl-2-methoxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;1-(cyclohexylmethyl)-6-(5-isopropyl-2-methoxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(5-isopropyl-2-methoxyphenyl)-1-neopentyl-1H-imidazo[4,5-b]pyrazin-2(3H)-one;1-isopropyl-6-(3-isopropylphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;1-isopropyl-6-(2-methoxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;(S)-3-(1-hydroxy-3-methylbutan-2-yl)-5-(5-isopropyl-2-methoxyphenyl)-1H-imidazo[4,5-b]pyridin-2(3H)-one;(R)-1-(2-hydroxy-1-phenylethyl)-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;(S)-1-(2-hydroxy-1-phenylethyl)-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;1-(1-phenylethyl)-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;1-benzhydryl-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;(S)-1-(1-phenylpropyl)-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;(R)-1-(1-phenylpropyl)-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(5-isopropyl-2-methoxyphenyl)-1-(tetrahydro-2H-pyran-3-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;1-(3-methoxybenzyl)-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;(R)-1-methyl-3-(1-phenylethyl)-5-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;(S)-1-methyl-3-(1-phenylethyl)-5-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;1-(cyclopentylmethyl)-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;1-(1-(2-fluorophenyl)ethyl)-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;1-(1-(4-fluorophenyl)ethyl)-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;1-cyclopentyl-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;1-(1-(3-fluorophenyl)ethyl)-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;1-(1-(3-methoxyphenyl)ethyl)-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;1-(1-(4-methoxyphenyl)ethyl)-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(quinolin-5-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(quinolin-5-yl)-1-(tetrahydro-2H-pyran-3-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;1-((1s,4s)-4-hydroxycyclohexyl)-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;1-((1r,4r)-4-hydroxycyclohexyl)-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(isoquinolin-5-yl)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;(R)-1-(1-phenylethyl)-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one;1-(1-phenylethyl)-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one;1-isopropyl-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;1-(1-(4-chlorophenyl)ethyl)-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;1-(1-(4-(methylsulfonyl)phenyl)ethyl)-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;1-(1-(pyridin-4-yl)ethyl)-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;5-methyl-1-((S)-1-phenylethyl)-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;5-methyl-1-((R)-1-phenylethyl)-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;1-(1-phenylethyl)-6-(quinolin-4-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(3-fluorophenyl)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(2-fluorophenyl)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;1-(1-phenylethyl)-6-(quinolin-6-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;1-(piperidin-4-ylmethyl)-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;1-(1-(pyridin-2-yl)ethyl)-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;1-(1-(pyridin-3-yl)ethyl)-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;1-((1s,4s)-4-(hydroxymethyl)cyclohexyl)-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;N-(4-(2-oxo-3-(1-phenylethyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)phenyl)methanesulfonamide;6-(3-(methylsulfonyl)phenyl)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(3-aminophenyl)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(3-(dimethylamino)phenyl)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;1-phenyl-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;1-(1-phenylethyl)-6-(4-(trifluoromethyl)phenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;N-(3-(2-oxo-3-(1-phenylethyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)phenyl)methanesulfonamide;6-(4-(methylsulfonyl)phenyl)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;3-(1-phenylethyl)-5-(quinolin-5-yl)oxazolo[5,4-b]pyrazin-2(3H)-one;1-(cyclopentylmethyl)-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one6-(4-hydroxyphenyl)-1-isopropyl-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(4-hydroxyphenyl)-1-isobutyl-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(4-hydroxyphenyl)-1-((tetrahydro-2H-pyran-3-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;1-(cyclohexylmethyl)-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;5-(3-Hydroxyphenyl)-3-(2-methoxyphenyl)-1H-imidazo[4,5-b]pyridin-2(3H)-one;4-(3-(3-Methoxybenzyl)-2-oxo-2,3-dihydrooxazolo[5,4-b]pyrazin-5-yl)-N-methylbenzamide;1-Cyclopentyl-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;1-Cyclohexyl-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;4-(3-(Cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzamide;Methyl4-(3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzoate;1-(Cyclohexylmethyl)-6-(pyridin-4-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;4-(3-(Cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)-N-methylbenzamide;1-(Cyclohexylmethyl)-6-(4-(hydroxymethyl)phenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;1-(Cyclohexylmethyl)-6-(pyridin-3-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;3-(Cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzonitrile;1-(Cyclohexylmethyl)-6-(1H-indol-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;4-(3-(Cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)-N-isopropylbenzamide;1-(2-Hydroxyethyl)-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;1-(Cyclohexylmethyl)-6-(1H-indol-6-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;3-(3-(Cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzamide;6-(4-(Aminomethyl)phenyl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(4-Hydroxyphenyl)-1-((1-methylpiperidin-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;;4-(3-(Cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzonitrile;1-((1s,4s)-4-Hydroxycyclohexyl)-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;1-(Cyclohexylmethyl)-6-(pyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;4-(3-(Cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)-N-ethylbenzamide;1-(Cyclohexylmethyl)-6-(4-(2-hydroxypropan-2-yl)phenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;1-(Cyclohexylmethyl)-6-(4-hydroxy-2-methylphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;4-(3-(Cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzoicacid;6-(4-Hydroxyphenyl)-1-(2-methoxyethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(4-Hydroxyphenyl)-1-(3-methoxypropyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(4-Hydroxyphenyl)-4-(3-methoxybenzyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(4-Hydroxyphenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(4-Hydroxyphenyl)-1-phenethyl-1H-imidazo[4,5-b]pyrazin-2(3H)-one;1-((1r,4r)-4-Hydroxycyclohexyl)-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(4-(1H-1,2,4-Triazol-3-yl)phenyl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;1-(Cyclohexylmethyl)-6-phenyl-1H-imidazo[4,5-b]pyrazin-2(3H)-one;1-(Cyclohexylmethyl)-6-(1H-pyrazol-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;1-(Cyclohexylmethyl)-6-(1H-pyrazol-4-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;1-(Cyclohexylmethyl)-6-(1-oxoisoindolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(3-(1H-Tetrazol-5-yl)phenyl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;1-(Cyclohexylmethyl)-6-(2-oxoindolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;1-(Cyclohexylmethyl)-6-(1H-indazol-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;1-(Cyclohexylmethyl)-6-(6-methoxypyridin-3-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(4-Hydroxyphenyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(4-Hydroxyphenyl)-1-(piperidin-4-ylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;1-(((1r,4r)-4-Aminocyclohexyl)methyl)-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;1-(Cyclohexylmethyl)-6-(6-hydroxypyridin-3-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;1-(Cyclohexylmethyl)-6-(2-methoxypyridin-4-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;4-(3-((1r,4r)-4-Hydroxycyclohexyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzamide;2-(4-(3-(Cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)phenyl)acetic acid;2-(4-(3-(Cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)phenyl)acetamide;1-(Cyclohexylmethyl)-6-(2-oxoindolin-6-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;4-(3-(Cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)-3-methylbenzoic acid;N-Methyl-4-(2-oxo-3-((tetrahydro-2H-pyran-4-yl)methyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzamide;4-(2-oxo-3-((Tetrahydro-2H-pyran-4-yl)methyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzamide;7-(4-Hydroxyphenyl)-1-(3-methoxybenzyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(4-(2-Hydroxypropan-2-yl)phenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(1H-Indol-5-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(4-(4H-1,2,4-Triazol-3-yl)phenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(1H-Benzo[d]imidazol-5-yl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;4-(2-oxo-3-(2-(Tetrahydro-2H-pyran-4-yl)ethyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzamide;6-(3-(2H-1,2,3-Triazol-4-yl)phenyl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(4-(1H-Imidazol-1-yl)phenyl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(4-(1H-1,2,4-Triazol-3-yl)phenyl)-1-((1r,4r)-4-hydroxycyclohexyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(4-(2H-tetrazol-5-yl)phenyl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;1-(Cyclohexylmethyl)-6-(2-hydroxypyridin-4-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(4-(1H-1,2,4-Triazol-3-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(4-(1H-Imidazol-2-yl)phenyl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(4-(1H-1,2,3-Triazol-1-yl)phenyl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(4-(2-Hydroxypropan-2-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;1-(Cyclohexylmethyl)-6-(4-(5-methyl-1H-1,2,4-triazol-3-yl)phenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(4-(1H-Pyrazol-3-yl)phenyl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(4-(1H-Pyrazol-4-yl)phenyl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(4-(5-(Aminomethyl)-1H-1,2,4-triazol-3-yl)phenyl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one hydrochloride;1-(Cyclohexylmethyl)-6-(4-(5-(trifluoromethyl)-1H-1,2,4-triazol-3-yl)phenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(4-Hydroxyphenyl)-1-((1r,4r)-4-methoxycyclohexyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(4-Hydroxyphenyl)-1-((tetrahydrofuran-2-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(3-(1H-1,2,4-Triazol-3-yl)phenyl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;1-((1r,4r)-4-(Hydroxymethyl)cyclohexyl)-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(4-Hydroxyphenyl)-1-((1s,4s)-4-methoxycyclohexyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(4-Hydroxyphenyl)-1-((1r,4r)-4-(methoxymethyl)cyclohexyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(1-Methyl-1H-pyrazol-4-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;1-(((1r,4r)-4-Hydroxycyclohexyl)methyl)-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(4-Hydroxyphenyl)-1-((tetrahydrofuran-3-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;1-(((1s,4s)-4-Hydroxycyclohexyl)methyl)-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(1H-Benzo[d]imidazol-5-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one hydrochloride;6-(4-(5-(Morpholinomethyl)-1H-1,2,4-triazol-3-yl)phenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(4-Hydroxyphenyl)-1-(3-(2-oxopyrrolidin-1-yl)propyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(4-Hydroxyphenyl)-1-(2-morpholinoethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-onehydrochloride;1-(Cyclohexylmethyl)-6-(4-(oxazol-5-yl)phenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(2-Methyl-1H-benzo[d]imidazol-5-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one hydrocholoride;6-(4-(5-(Methoxymethyl)-1H-1,2,4-triazol-3-yl)phenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;1-((1s,4s)-4-(Hydroxymethyl)cyclohexyl)-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(3-Methyl-1H-pyrazol-4-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(1H-Pyrazol-4-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(2-Amino-1H-benzo[d]imidazol-5-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one di hydrochloride;6-(4-(5-(2-Hydroxypropan-2-yl)-1H-1,2,4-triazol-3-yl)phenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(4-(5-Isopropyl-1H-1,2,4-triazol-3-yl)phenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;4-(2-Methoxy-1-(2-morpholinoethyl)-1H-imidazo[4,5-b]pyrazin-6-yl)benzamidehydrochloride;4-(1-((1s,4s)-4-Hydroxycyclohexyl)-2-methoxy-1H-imidazo[4,5-b]pyrazin-6-yl)benzamide;6-(4-Hydroxyphenyl)-1-((1s,4s)-4-(methoxymethyl)cyclohexyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(3H-imidazo[4,5-b]pyridin-6-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;1-(2-(2,2-Dimethyltetrahydro-2H-pyran-4-yl)ethyl)-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(4-(1H-Pyrazol-1-yl)phenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(4-(4H-1,2,4-Triazol-3-yl)phenyl)-1-(2-morpholinoethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(4-(1H-Benzo[d]imidazol-2-yl)phenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(4-(1H-Imidazol-2-yl)phenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one hydrochloride;6-(4-(5-(Hydroxymethyl)-1H-1,2,4-triazol-3-yl)phenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(4-(1H-Imidazol-5-yl)phenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one hydrochloride;6-(4-Hydroxyphenyl)-1-((5-oxopyrrolidin-2-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(4-(4,5-Dimethyl-1H-imidazol-2-yl)phenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(4-(1H-1,2,4-Triazol-5-yl)phenyl)-1-(((1s,4s)-4-methoxycyclohexyl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(4-(1H-1,2,4-Triazol-5-yl)phenyl)-1-(((1r,4r)-4-methoxycyclohexyl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(6-(1H-1,2,4-Triazol-3-yl)pyridin-3-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(4-(1H-1,2,4-Triazol-3-yl)phenyl)-1-(2-(2-oxopyrrolidin-1-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(4-(5-((dimethylamino)methyl)-1H-1,2,4-triazol-3-yl)phenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(4-Hydroxyphenyl)-1-(pyrrolidin-2-ylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-onehydrochloride;6-(2-Aminobenzimidazol-5-yl)-1-(cyclohexylmethyl)-4-imidazolino[4,5-b]pyrazin-2-onedi hydrochloride;6-(2-(Dimethylamino)-1H-benzo[d]imidazol-5-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)- 1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(4-Hydroxyphenyl)-1-(piperidin-3-ylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(4-(4H-1,2,4-triazol-3-yl)phenyl)-1-(2-(piperidin-1-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one hydrochloride;1-(Cyclohexylmethyl)-6-(2-(methylamino)pyrimidin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(3-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;1-(Cyclohexylmethyl)-6-(2-(2-methoxyethylamino)pyrimidin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(4-(5-((methylamino)methyl)-1H-1,2,4-triazol-3-yl)phenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(4-(5-Oxopyrrolidin-2-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(4-(5-methyl-1H-1,2,4-triazol-3-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(4-(1H-imidazol-2-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(4-(4H-1,2,4-triazol-3-yl)phenyl)-1-(2-methyl-2-morpholinopropyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(4-(4H-1,2,4-Triazol-3-yl)phenyl)-1-(1-morpholinopropan-2-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(4-(Pyrrolidin-2-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(4-(5-(aminomethyl)-1H-1,2,4-triazol-3-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(5-(Hydroxymethyl)thiophen-2-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;(1r,4r)-4-(6-(4-Hydroxyphenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-1-yl)cyclohexanecarboxamide;(1s,4s)-4-(6-(4-Hydroxyphenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-1-yl)cyclohexanecarboxamide;6-(4-(5-methyl-1H-1,2,4-triazol-3-yl)phenyl)-1-(2-morpholinoethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(4-(5-Oxopyrrolidin-3-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(4-(Pyrrolidin-3-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(1H-benzo[d]imidazol-5-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(3-(Hydroxymethyl)thiophen-2-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(5-(2-Hydroxyethyl)thiophen-2-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;1-(Cyclohexylmethyl)-6-(pyrimidin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(6-Fluoropyridin-3-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(6-Aminopyridin-3-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(4-(5-methyl-1H-imidazol-2-yl)phenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(4-(5-Methyl-1H-1,2,4-triazol-3-yl)phenyl)-1-(2-(2-oxopyrrolidin-1-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(6-(Methylamino)pyridin-3-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(2-aminopyrimidin-5-yl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(4-(2-hydroxypropan-2-yl)phenyl)-1-(((1r,4r)-4-methoxycyclohexyl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(4-hydroxyphenyl)-1-((1-methylpiperidin-3-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;1-(cyclohexylmethyl)-6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(4-(hydroxymethyl)thiophen-2-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(1H-benzo[d]imidazol-6-yl)-1-(((1r,4r)-4-methoxycyclohexyl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(4-(4,5-dimethyl-1H-imidazol-2-yl)phenyl)-1-(2-morpholinoethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(4-(4H-1,2,4-triazol-3-yl)phenyl)-1-(2-morpholino-2-oxoethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(4-(4H-1,2,4-triazol-3-yl)phenyl)-3-(cyclohexylmethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-imidazo[4,5-b]pyridin-2(3H)-one;(R)-6-(4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;(S)-6-(4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;(1r,4r)-4-(6-(4-(2-hydroxypropan-2-yl)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-1-yl)cyclohexanecarboxamide;6-(3-Methyl-4-(1H-1,2,4-Triazol-3-yl)phenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-B]pyrazin-2(3H)-one;6-(4-(1H-imidazol-2-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(4-(5-(Aminomethyl)-1H-1,2,4-triazol-3-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(1H-benzo[d]imidazol-5-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(2-Aminopyrimidin-5-yl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(4-Hydroxyphenyl)-1-((1-methylpiperidin-2-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one hydrochloride;6-(3-Methyl-4-(1H-1,2,4-Triazol-3-yl)phenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-B]pyrazin-2(3H)-one;1-(Cyclohexylmethyl)-6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(6-(2-Hydroxypropan-2-yl)pyridin-3-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(6-(2-Hydroxypropan-2-yl)pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;6-(4-(4H-1,2,4-Triazol-3-yl)phenyl)-1-(2-morpholino-2-oxoethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;(R)-6-(4-(4H-1,2,4-Triazol-3-yl)phenyl)-3-(cyclohexylmethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;(R)-6-(4-(1H-1,2,4-Triazol-3-yl)phenyl)-1-(1-phenylethyl)-1H-imidazo[4,5-B]pyrazin-2(3H)-one;(S)-6-(4-(4H-1,2,4-Triazol-3-yl)phenyl)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;(1r,4r)-4-(6-(4-(2-Hydroxypropan-2-yl)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-1-yl)cyclohexanecarboxamide; and6-(4-(5-Methyl-1H-1,2,4-triazol-3-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one, and pharmaceutically acceptable salts,clathrates, solvates, stereoisomers, tautomers, and prodrugs thereof.

In one embodiment, the TOR kinase inhibitors include compounds havingthe following formula (II):

and pharmaceutically acceptable salts, clathrates, solvates,stereoisomers, tautomers, and prodrugs thereof, wherein:

R¹ is substituted or unsubstituted C₁₋₈alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl;

—X-A-B—Y— taken together form —N(R²)CH₂C(O)NH—, —N(R²)C(O)CH₂NH—,—N(R²)C(O)NH—, —N(R²)C═N—, or —C(R²)═CHNH—;

L is a direct bond, NH or O;

R² is substituted or unsubstituted C₁₋₈alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl; and

R³ and R⁴ are independently H or C₁₋₈alkyl.

In one embodiment, the TOR kinase inhibitors of formula (II) are thosewherein —X-A-B—Y— taken together form —N(R²)CH₂C(O)NH—.

In another embodiment, the TOR kinase inhibitors of formula (II) arethose wherein —X-A-B—Y— taken together form —N(R²)C(O)CH₂NH—.

In another embodiment, the TOR kinase inhibitors of formula (II) arethose wherein —X-A-B—Y— taken together form —N(R²)C(O)NH—.

In another embodiment, the TOR kinase inhibitors of formula (II) arethose wherein —X-A-B—Y— taken together form —N(R²)C═N—.

In another embodiment, the TOR kinase inhibitors of formula (II) arethose wherein —X-A-B—Y— taken together form —C(R²)═CHNH—.

In another embodiment, the TOR kinase inhibitors of formula (II) arethose wherein L is a direct bond.

In another embodiment, the TOR kinase inhibitors of formula (II) arethose wherein R¹ is substituted aryl, such as substituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (II) arethose wherein R¹ is substituted or unsubstituted heteroaryl, such assubstituted or unsubstituted pyridine, substituted or unsubstitutedindole or substituted or unsubstituted quinoline.

In another embodiment, the TOR kinase inhibitors of formula (II) arethose wherein R¹ is substituted or unsubstituted cycloalkyl, such assubstituted or unsubstituted cyclopentyl.

In another embodiment, the TOR kinase inhibitors of formula (II) arethose wherein —X-A-B—Y— taken together form —N(R²)C(O)NH— and R¹ issubstituted aryl, such as phenyl.

In another embodiment, the TOR kinase inhibitors of formula (II) arethose wherein —X-A-B—Y— taken together form —N(R²)C(O)NH— and R¹ issubstituted or unsubstituted heteroaryl, such as substituted orunsubstituted pyridine, substituted or unsubstituted indole orsubstituted or unsubstituted quinoline.

In another embodiment, the TOR kinase inhibitors of formula (II) arethose wherein —X-A-B—Y— taken together form —N(R²)C(O)NH— and R¹ issubstituted or unsubstituted cycloalkyl, such as substituted orunsubstituted cyclopentyl.

In another embodiment, the TOR kinase inhibitors of formula (II) arethose wherein R² is substituted C₁₋₈alkyl, such as —CH₂C₆H₅.

In another embodiment, the TOR kinase inhibitors of formula (II) arethose wherein R² is unsubstituted C₁₋₈alkyl, such as unsubstitutedmethyl.

In another embodiment, the TOR kinase inhibitors of formula (II) arethose wherein R² is substituted or unsubstituted aryl, such assubstituted or unsubstituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (II) arethose wherein R² is substituted aryl, such as halo, haloalkyl or alkoxysubstituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (II) arethose wherein R² is substituted or unsubstituted cycloalkyl, such assubstituted or unsubstituted cyclohexyl or substituted or unsubstitutedcycloheptyl.

In another embodiment, the TOR kinase inhibitors of formula (II) arethose wherein R² is substituted heterocyclylalkyl, such as substitutedpiperidine.

In another embodiment, the TOR kinase inhibitors of formula (II) arethose wherein R³ and R⁴ are H.

In another embodiment, the TOR kinase inhibitors of formula (II) arethose wherein —X-A-B—Y— taken together form —N(R²)C(O)NH— and R² isunsubstituted aryl, such as unsubstituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (II) arethose wherein —X-A-B—Y— taken together form —N(R²)C(O)NH—, R¹ issubstituted or unsubstituted heteroaryl, such as substituted orunsubstituted pyridine, and R² is substituted or unsubstituted aryl,such as substituted or unsubstituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (II) arethose wherein —X-A-B—Y— taken together form —N(R²)C(O)NH—, R¹ issubstituted or unsubstituted heteroaryl, such as substituted orunsubstituted pyridine, R² is substituted or unsubstituted aryl, such assubstituted or unsubstituted phenyl, and R³ and R⁴ are H.

In another embodiment, the TOR kinase inhibitors of formula (II) arethose wherein —X-A-B—Y— taken together form —N(R²)C(O)NH—, L is a directbond, R¹ is substituted or unsubstituted heteroaryl, such as substitutedor unsubstituted pyridine, R² is substituted or unsubstituted aryl, suchas substituted or unsubstituted phenyl, and R³ and R⁴ are H.

In another embodiment, the TOR kinase inhibitors of formula (II) arethose wherein —X-A-B—Y— taken together form —N(R²)C(O)NH—, R¹ issubstituted or unsubstituted aryl, such as substituted or unsubstitutedphenyl, and R² is substituted or unsubstituted aryl, such as substitutedor unsubstituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (II) arethose wherein —X-A-B—Y— taken together form —N(R²)C(O)NH—, R¹ issubstituted or unsubstituted aryl, such as substituted or unsubstitutedphenyl, R² is substituted or unsubstituted aryl, such as substituted orunsubstituted phenyl, and R³ and R⁴ are H.

In another embodiment, the TOR kinase inhibitors of formula (II) arethose wherein —X-A-B—Y— taken together form —N(R²)C(O)NH—, L is a directbond, R¹ is substituted or unsubstituted aryl, such as substituted orunsubstituted phenyl, R² is substituted or unsubstituted aryl, such assubstituted or unsubstituted phenyl, and R³ and R⁴ are H.

In another embodiment, the TOR kinase inhibitors of formula (II) arethose wherein —X-A-B—Y— taken together form —N(R²)C(O)NH—, R¹ issubstituted or unsubstituted heteroaryl, L is a direct bond and R² issubstituted or unsubstituted C₁₋₈alkyl or substituted or unsubstitutedcycloalkyl.

In another embodiment, the TOR kinase inhibitors of formula (II) arethose wherein —X-A-B—Y— taken together form —N(R²)C(O)NH—, R¹ issubstituted or unsubstituted aryl, L is a direct bond and R² issubstituted or unsubstituted C₁₋₈alkyl or substituted or unsubstitutedcycloalkyl.

In another embodiment, the TOR kinase inhibitors of formula (II) do notinclude8,9-dihydro-8-oxo-9-phenyl-2-(3-pyridinyl)-7H-purine-6-carboxamide,8,9-dihydro-8-oxo-9-phenyl-2-(3-pyridinyl)-7H-purine-6-carboxamide,8,9-dihydro-8-oxo-9-phenyl-2-(3-pyridinyl)-7H-purine-6-carboxamide,2-(4-cyanophenyl)-8-oxo-9-phenyl-8,9-dihydro-7H-purine-6-carboxamide,2-(4-nitrophenyl)-8-oxo-9-phenyl-8,9-dihydro-7H-purine-6-carboxamide,9-benzyl-2-(4-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide,2-methyl-8-oxo-9-phenyl-8,9-dihydro-7H-purine-6-carboxamide,9-benzyl-9H-purine-2,6-dicarboxamide,9-[2,3-bis[(benzoyloxy)methyl]cyclobutyl]-2-methyl-9H-Purine-6-carboxamide,9-benzyl-2-methyl-9H-purine-6-carboxamide,9-(2-hydroxyethyl)-2-methyl-9H-purine-6-carboxamide,9-(2-hydroxyethyl)-2-(trifluoromethyl)-9H-purine-6-carboxamide,9-(2-hydroxyethyl)-2-(prop-1-enyl)-9H-purine-6-carboxamide,9-(2-hydroxyethyl)-2-phenyl-9H-purine-6-carboxamide,9-(3-hydroxypropyl)-2-methyl-9H-purine-6-carboxamide,9-(3-hydroxypropyl)-2-(trifluoromethyl)-9H-purine-6-carboxamide,2-methyl-9-phenylmethyl-9H-purine-6-carboxamide or2-methyl-9-β-D-ribofuranosyl-9H-purine-6-carboxamide.

In another embodiment, the TOR kinase inhibitors of formula (II) do notinclude compounds wherein R² is a substituted furanoside.

In another embodiment, the TOR kinase inhibitors of formula (II) do notinclude compounds wherein R² is a substituted or unsubstitutedfuranoside.

In another embodiment, the TOR kinase inhibitors of formula (II) do notinclude (2′R)-2′-deoxy-2′-fluoro-2′-C-methyl nucleosides.

In one embodiment, the TOR kinase inhibitors include compounds havingthe following formula (IIa):

and pharmaceutically acceptable salts, clathrates, solvates,stereoisomers, tautomers, and prodrugs thereof, wherein:

R¹ is substituted or unsubstituted C₁₋₈alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl;

R² is substituted or unsubstituted C₁₋₈alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl; and

R³ and R⁴ are independently H or C₁₋₈alkyl.

In one embodiment, the TOR kinase inhibitors of formula (IIa) are thosewherein R¹ is substituted aryl, substituted or unsubstituted heteroaryl,such as substituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (IIa) arethose wherein R¹ is substituted or unsubstituted heteroaryl, such assubstituted or unsubstituted pyridine, substituted or unsubstitutedindole or substituted or unsubstituted quinoline.

In another embodiment, the TOR kinase inhibitors of formula (IIa) arethose wherein R¹ is substituted or unsubstituted cycloalkyl, such assubstituted or unsubstituted cyclopentyl.

In another embodiment, the TOR kinase inhibitors of formula (IIa) arethose wherein R² is substituted C₁₋₈alkyl, such as —CH₂C₆H₅.

In another embodiment, the TOR kinase inhibitors of formula (IIa) arethose wherein R² is unsubstituted C₁₋₈alkyl, such as unsubstitutedmethyl.

In another embodiment, the TOR kinase inhibitors of formula (IIa) arethose wherein R² is substituted or unsubstituted aryl, such assubstituted or unsubstituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (IIa) arethose wherein R² is substituted aryl, such as halo, haloalkyl or alkoxysubstituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (IIa) arethose wherein R² is substituted or unsubstituted cycloalkyl, such assubstituted or unsubstituted cyclohexyl or substituted or unsubstitutedcycloheptyl.

In another embodiment, the TOR kinase inhibitors of formula (IIa) arethose wherein R² is substituted heterocyclylalkyl, such as substitutedpiperidine.

In another embodiment, the TOR kinase inhibitors of formula (IIa) arethose wherein R³ and R⁴ are H.

In another embodiment, the TOR kinase inhibitors of formula (IIa) do notinclude8,9-dihydro-8-oxo-9-phenyl-2-(3-pyridinyl)-7H-Purine-6-carboxamide,8,9-dihydro-8-oxo-9-phenyl-2-(3-pyridinyl)-7H-Purine-6-carboxamide,8,9-dihydro-8-oxo-9-phenyl-2-(3-pyridinyl)-7H-Purine-6-carboxamide,2-(4-cyanophenyl)-8-oxo-9-phenyl-8,9-dihydro-7H-purine-6-carboxamide,2-(4-nitrophenyl)-8-oxo-9-phenyl-8,9-dihydro-7H-purine-6-carboxamide,9-benzyl-2-(4-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide,9-phenylmethyl-9H-purine-2,6-dicarboxamide, or2-methyl-8-oxo-9-phenyl-8,9-dihydro-7H-purine-6-carboxamide.

In another embodiment, the TOR kinase inhibitors of formula (IIa) do notinclude compounds wherein R² is a substituted furanoside.

In another embodiment, the TOR kinase inhibitors of formula (IIa) do notinclude compounds wherein R² is a substituted or unsubstitutedfuranoside.

In another embodiment, the TOR kinase inhibitors of formula (IIa) do notinclude (2′R)-2′-deoxy-2′-fluoro-2′-C-methyl nucleosides.

In one embodiment, the TOR kinase inhibitors include compounds havingthe following formula (IIb):

and pharmaceutically acceptable salts, clathrates, solvates,stereoisomers, tautomers, and prodrugs thereof, wherein:

is —C(R²)═CH—NH— or —N(R²)—CH═N—;

R¹ is substituted or unsubstituted C₁₋₈alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl;

R² is substituted or unsubstituted C₁₋₈alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl; and

R³ and R⁴ are independently H or C₁₋₈alkyl.

In one embodiment, the TOR kinase inhibitors of formula (IIb) are thosewherein R¹ is substituted aryl, such as substituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (IIb) arethose wherein R¹ is substituted or unsubstituted heteroaryl, such assubstituted or unsubstituted pyridine, substituted or unsubstitutedindole or substituted or unsubstituted quinoline.

In another embodiment, the TOR kinase inhibitors of formula (IIb) arethose wherein R¹ is substituted or unsubstituted cycloalkyl, such assubstituted or unsubstituted cyclopentyl.

In another embodiment, the TOR kinase inhibitors of formula (IIb) arethose wherein R² is substituted C₁₋₈alkyl, such as —CH₂C₆H₅.

In another embodiment, the TOR kinase inhibitors of formula (IIb) arethose wherein R² is unsubstituted C₁₋₈alkyl, such as unsubstitutedmethyl.

In another embodiment, the TOR kinase inhibitors of formula (IIb) arethose wherein R² is substituted or unsubstituted aryl, such assubstituted or unsubstituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (IIb) arethose wherein R² is substituted aryl, such as halo, haloalkyl or alkoxysubstituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (IIb) arethose wherein R² is substituted or unsubstituted cycloalkyl, such assubstituted or unsubstituted cyclohexyl or substituted or unsubstitutedcycloheptyl.

In another embodiment, the TOR kinase inhibitors of formula (IIb) arethose wherein R² is substituted heterocyclylalkyl, such as substitutedpiperidine.

In another embodiment, the TOR kinase inhibitors of formula (IIb) arethose wherein R³ and R⁴ are H.

In another embodiment, the TOR kinase inhibitors of formula (IIb) arethose wherein

is —C(R²)═CH—NH— and R² is substituted aryl, such as substituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (IIb) arethose wherein

is —N(R²)—CH═N— and R² is substituted aryl, such as substituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (IIb) arethose wherein R¹ is substituted aryl, such as phenyl, and R² issubstituted aryl, such as substituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (IIb) do notinclude 9-benzyl-9H-purine-2,6-dicarboxamide,9-[2,3-bis[(benzoyloxy)methyl]cyclobutyl]-2-methyl-9H-Purine-6-carboxamide,9-benzyl-2-methyl-9H-purine-6-carboxamide,9-(2-hydroxyethyl)-2-methyl-9H-purine-6-carboxamide,9-(2-hydroxyethyl)-2-(trifluoromethyl)-9H-purine-6-carboxamide,9-(2-hydroxyethyl)-2-(prop-1-enyl)-9H-purine-6-carboxamide,9-(2-hydroxyethyl)-2-phenyl-9H-purine-6-carboxamide,9-(3-hydroxypropyl)-2-methyl-9H-purine-6-carboxamide,9-(3-hydroxypropyl)-2-(trifluoromethyl)-9H-purine-6-carboxamide,9-phenylmethyl-9H-purine-2,6-dicarboxamide,2-methyl-9-phenylmethyl-9H-purine-6-carboxamide or2-methyl-9-β-D-ribofuranosyl-9H-purine-6-carboxamide.

In another embodiment, the TOR kinase inhibitors of formula (IIb) do notinclude compounds wherein R² is substituted cyclobutyl when

is —N(R²)—CH═N—.

In another embodiment, the TOR kinase inhibitors of formula (IIb) do notinclude compounds wherein R² is a substituted furanoside when

is —N(R²)—CH═N—.

In another embodiment, the TOR kinase inhibitors of formula (IIb) do notinclude compounds wherein R² is substituted pyrimidine when

is —C(R²)═CH—NH—.

In another embodiment, the TOR kinase inhibitors of formula (IIb) do notinclude compounds wherein R² is substituted oxetane when

is —N(R²)—CH═N—.

In another embodiment, the TOR kinase inhibitors of formula (IIb) do notinclude compounds wherein R² is substituted cyclopentyl or aheterocyclopentyl when

is —N(R²)—CH═N—.

In one embodiment, the TOR kinase inhibitors include compounds havingthe following formula (IIc):

and pharmaceutically acceptable salts, clathrates, solvates,stereoisomers, tautomers, and prodrugs thereof, wherein:

R¹ is substituted or unsubstituted C₁₋₈alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl;

R² is substituted or unsubstituted C₁₋₈alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl; and

R³ and R⁴ are independently H or C₁₋₈alkyl.

In one embodiment, the TOR kinase inhibitors of formula (IIc) are thosewherein R¹ is substituted aryl, such as substituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (IIc) arethose wherein R¹ is substituted or unsubstituted heteroaryl, such assubstituted or unsubstituted pyridine, substituted or unsubstitutedindole or substituted or unsubstituted quinoline.

In another embodiment, the TOR kinase inhibitors of formula (IIc) arethose wherein R¹ is substituted or unsubstituted cycloalkyl, such assubstituted or unsubstituted cyclopentyl.

In another embodiment, the TOR kinase inhibitors of formula (IIc) arethose wherein R² is substituted C₁₋₈alkyl, such as —CH₂C₆H₅.

In another embodiment, the TOR kinase inhibitors of formula (IIc) arethose wherein R² is unsubstituted C₁₋₈alkyl, such as unsubstitutedmethyl.

In another embodiment, the TOR kinase inhibitors of formula (IIc) arethose wherein R² is substituted or unsubstituted aryl, such assubstituted or unsubstituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (IIc) arethose wherein R² is substituted aryl, such as halo, haloalkyl or alkoxysubstituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (IIc) arethose wherein R² is substituted or unsubstituted cycloalkyl, such assubstituted or unsubstituted cyclohexyl or substituted or unsubstitutedcycloheptyl.

In another embodiment, the TOR kinase inhibitors of formula (IIc) arethose wherein R² is substituted heterocyclylalkyl, such as substitutedpiperidine.

In another embodiment, the TOR kinase inhibitors of formula (IIc) arethose wherein R³ and R⁴ are H.

In one embodiment, the TOR kinase inhibitors include compounds havingthe following formula (IId):

and pharmaceutically acceptable salts, clathrates, solvates,stereoisomers, tautomers, and prodrugs thereof, wherein:

R¹ is substituted or unsubstituted C₁₋₈alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl;

R² is substituted or unsubstituted C₁₋₈alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl; and

R³ and R⁴ are independently H or C₁₋₈alkyl.

In one embodiment, the TOR kinase inhibitors of formula (IId) are thosewherein R¹ is substituted aryl, such as substituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (IId) arethose wherein R¹ is substituted or unsubstituted heteroaryl, such assubstituted or unsubstituted pyridine, substituted or unsubstitutedindole or substituted or unsubstituted quinoline.

In another embodiment, the TOR kinase inhibitors of formula (IId) arethose wherein R¹ is substituted or unsubstituted cycloalkyl, such assubstituted or unsubstituted cyclopentyl.

In another embodiment, the TOR kinase inhibitors of formula (IId) arethose wherein R² is substituted C₁₋₈alkyl, such as —CH₂C₆H₅.

In another embodiment, the TOR kinase inhibitors of formula (IId) arethose wherein R² is unsubstituted C₁₋₈alkyl, such as unsubstitutedmethyl.

In another embodiment, the TOR kinase inhibitors of formula (IId) arethose wherein R² is substituted or unsubstituted aryl, such assubstituted or unsubstituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (IId) arethose wherein R² is substituted aryl, such as halo, haloalkyl or alkoxysubstituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (IId) arethose wherein R² is substituted or unsubstituted cycloalkyl, such assubstituted or unsubstituted cyclohexyl or substituted or unsubstitutedcycloheptyl.

In another embodiment, the TOR kinase inhibitors of formula (IId) arethose wherein R² is substituted heterocyclylalkyl, such as substitutedpiperidine.

In another embodiment, the TOR kinase inhibitors of formula (IId) arethose wherein R³ and R⁴ are H.

Representative TOR kinase inhibitors of formula (II) include compoundsfrom Table B.

TABLE B9-benzyl-8-oxo-2-(pyridin-3-yl)-8,9-dihydro-7H-purine-6-carboxamide;N-methyl-8-oxo-9-phenyl-2-(pyridin-3-yl)-8,9-dihydro-7H-purine-6-carboxamide;8-oxo-9-phenyl-2-(pyridin-2-yl)-8,9-dihydro-7H-purine-6-carboxamide;2-(2-chloropyridin-3-yl)-8-oxo-9-phenyl-8,9-dihydro-7H-purine-6-carboxamide;2-(2-methoxypyridin-3-yl)-8-oxo-9-phenyl-8,9-dihydro-7H-purine-6-carboxamide;N,N-dimethyl-8-oxo-9-phenyl-2-(pyridin-3-yl)-8,9-dihydro-7H-purine-6-carboxamide;9-methyl-8-oxo-2-(pyridin-3-yl)-8,9-dihydro-7H-purine-6-carboxamide;2-(4-hydroxyphenyl)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;2-(3-hydroxyphenyl)-8-oxo-9-o-tolyl-8,9-dihydro-7H-purine-6-carboxamide;2-(1H-indol-4-yl)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;2-(1H-indol-6-yl)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;2-(3-hydroxyphenyl)-9-(4-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;2-(2-hydroxypyridin-4-yl)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;9-(2-chlorophenyl)-2-(3-hydroxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;9-(2-fluorophenyl)-2-(3-hydroxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;9-(2,6-difluorophenyl)-2-(3-hydroxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;9-cycloheptyl-8-oxo-2-(pyridin-3-yl)-8,9-dihydro-7H-purine-6-carboxamide;9-(2-methoxyphenyl)-8-oxo-2-(quinolin-5-yl)-8,9-dihydro-7H-purine-6-carboxamide;2-cyclopentyl-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;9-(2-methoxyphenyl)-8-oxo-2-(3-(trifluoromethyl)phenyl)-8,9-dihydro-7H-purine-6-carboxamide;9-(2-methoxyphenyl)-2-(6-methoxypyridin-3-yl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;2-(3-hydroxyphenyl)-8-oxo-9-(4-(trifluoromethyl)phenyl)-8,9-dihydro-7H-purine-6-carboxamide;9-benzyl-2-(3-hydroxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;2-(3-hydroxyphenyl)-8-oxo-9-(2-(trifluoromethoxy)phenyl)-8,9-dihydro-7H-purine-6-carboxamide;9-(2,4-dichlorophenyl)-2-(3-hydroxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;9-(2-methoxyphenyl)-2-(3-nitrophenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;2-(3-cyanophenyl)-8-oxo-9-phenyl-8,9-dihydro-7H-purine-6-carboxamide;9-(3-fluorophenyl)-2-(3-hydroxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;9-(2-methoxyphenyl)-8-oxo-2-(2-(trifluoromethyl)phenyl)-8,9-dihydro-7H-purine-6-carboxamide;2-(5-fluoropyridin-3-yl)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;2-(1-benzylpiperidin-4-yl)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide; benzyl4-(6-carbamoyl-8-oxo-2-(pyridin-3-yl)-7H-purin-9(8H)-yl)piperidine-1-carboxylate;9-cyclohexyl-2-(3-hydroxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;9-(2-methoxyphenyl)-8-oxo-2-(3-(trifluoromethoxy)phenyl)-8,9-dihydro-7H-purine-6-carboxamide; 9-phenyl-2-(pyridin-3-yl)-9H-purine-6-carboxamide;6-oxo-8-phenyl-2-(pyridin-3-yl)-5,6,7,8-tetrahydropteridine-4-carboxamide;6-oxo-8-phenyl-2-(pyridin-4-yl)-5,6,7,8-tetrahydropteridine-4-carboxamide;2-(3-aminophenyl)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;2-(3-hydroxyphenyl)-9-(2-methoxyphenyl)-9H-purine-6-carboxamide;9-Cyclopentyl-2-(3-hydroxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;9-tert-Butyl-2-(3-hydroxy-phenyl)-8-oxo-8,9-dihydo-7H-purine-6-carboxamide;[2-(3-Hydroxyphenyl)-9-(2-methoxyphenyl)-8-oxo(7-hydropurin-6-yl)]-N-methylcarbox-amide; 2-phenyl-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide;[2-(3-Hydroxyphenyl)-9-(2-methoxyphenyl)-8-oxo(7-hydropurin-6-yl)]-N,N-dimethylcarboxamide;2-(3-Hydroxyphenylamino)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;2-(4-Hydroxyphenylamino)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;9-(trans-4-Hydroxycyclohexyl)-2-(3-hydroxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;9-(trans-4-Hydroxycyclohexyl)-8-oxo-2-(pyridin-3-yl)-8,9-dihydro-7H-purine-6-carboxamide;9-(trans-4-Hydroxycyclohexyl)-2-(3-hydroxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;9-(trans-4-Hydroxycyclohexyl)-8-oxo-2-(pyridin-3-yl)-8,9-dihydro-7H-purine-6-carboxamide;2-(3-Hydroxyphenylamino)-9-(2-methoxyphenyl)-9H-purine-6-carboxamide;9-Isopropyl-2-(3-hydroxy-phenyl)-8-oxo-8,9-dihydo-7H-purine-6-carboxamide;Methyl4-(6-carbamoyl-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purin-2-yl)benzoate;2-(2-Chloro-3-hydroxyphenyl)-9-(2-methoxyphenyl)-8-oxo-7-hydropurine-6-carboxamide;2-(3-Cyanophenyl)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;2-(2-Hydroxyphenylamino)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;2-(3-Hydroxyphenyl)-9-(4-methoxy-2-methylphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;2-(3-Hydroxyphenyl)-8-oxo-9-(2-(trifluoromethyl)phenyl)-8,9-dihydro-7H-purine-6-carboxamide;2-(4-Cyano-phenyl)-9-(2-methoxy-phenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;4-[6-Carbamoyl-9-(2-methoxy-phenyl)-8-oxo-8,9-dihydro-7H-purin-2-yl]-benzoicacid; Methyl3-(6-carbamoyl-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purin-2-yl)benzoate;3-(6-Carbamoyl-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purin-2-yl)benzoicacid;2-(3-Hydroxyphenyl)-9-(2-isopropylphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;2-(1H-Indazol-6-yl)-9-(2-methoxyphenyl)-8-oxo-7-hydropurine-6-carboxamide;2-(4-Carbamoylphenyl)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;9-(2-Ethylphenyl)-2-(3-hydroxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;9-(2,5-Dichlorophenyl)-2-(3-hydroxyphenyl)-8-oxo-7-hydropurine-6-carboxamide;2-(3-Carbamoylphenyl)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;9-(2,6-Dichlorophenyl)-2-(3-hydroxyphenyl)-8-oxo-7-hydropurine-6-carboxamide;2-(2-Hydroxyphenyl)-9-(2-methoxyphenyl)purine-6-carboxamide;2-(1H-Indazol-5-yl)-9-(2-methoxyphenyl)-8-oxo-7-hydropurine-6-carboxamide;9-(2,3-Dichlorophenyl)-2-(3-hydroxyphenyl)-8-oxo-7-hydropurine-6-carboxamide;2-[4-(Hydroxymethyl)phenyl]-9-(2-methoxyphenyl)-8-oxo-7-hydropurine-6-carbox-amide;2-[3-(Hydroxymethyl)phenyl]-9-(2-methoxyphenyl)-8-oxo-7-hydropurine-6-carbox-amide;9-(2-Methoxyphenyl)-8-oxo-2-(pyridin-4-yl)-8,9-dihydro-7H-purine-6-carboxamide;2-(4-Fluoro-3-hydroxyphenyl)-9-(2-methoxyphenyl)-8-oxo-7-hydropurine-6-carbox-amide;2-(2-Fluoro-3-hydroxyphenyl)-9-(2-methoxyphenyl)-8-oxo-7-hydropurine-6-carbox-amide;2-[4-(1-Hydroxy-isopropyl)phenyl]-9-(2-methoxyphenyl)-8-oxo-7-hydropurine-6-carboxamide;2-[3-(1-Hydroxy-isopropyl)phenyl]-9-(2-methoxyphenyl)-8-oxo-7-hydropurine-6-carboxamide;9-(2-Methoxyphenyl)-2-(2-nitrophenyl)-8-oxo-7-hydropurine-6-carboxamide;9-(2-Methoxyphenyl)-2-(4-nitrophenyl)-8-oxo-7-hydropurine-6-carboxamide;9-(2-Methoxyphenyl)-2-(2-nitrophenyl)-8-oxo-7-hydropurine-6-carboxamide;9-(2,4-Difluorophenyl)-2-(3-hydroxyphenyl)-8-oxo-7-hydropurine-6-carboxamide;9-(2-Methoxyphenyl)-2-{3-[(methylsulfonyl)amino]phenyl}-8-oxo-7-hydropurine-6-carboxamide;9-(4-Chloro-2-fluorophenyl)-2-(3-hydroxyphenyl)-8-oxo-7-hydropurine-6-carboxamide;9-(2-Chlorophenyl)-8-oxo-2-(3-pyridyl)-7-hydropurine-6-carboxamide;8-Oxo-2-(3-pyridyl)-9-[2-(trifluoromethyl)phenyl]-7-hydropurine-6-carboxamide;9-(3-Chloro-2-fluorophenyl)-2-(3-hydroxyphenyl)-8-oxo-7-hydropurine-6-carboxamide;9-(2-Fluoro-3-trifluoromethylphenyl)-2-(3-hydroxyphenyl)-8-oxo-7-hydropurine-6-carboxamide;9-(2,3,4-Trifluorophenyl)-2-(3-hydroxyphenyl)-8-oxo-7-hydropurine-6-carboxamide;2-(1H-Benzo[d]imidazol-6-yl)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;2-[3-(Acetylamino)phenyl]-9-(2-methoxyphenyl)-8-oxo-7-hydropurine-6-carboxamide;2-(3-hydroxyphenyl)-8-(2-methoxyphenyl)-6-oxo-5,6,7,8-tetrahydropteridine-4-carbox-amide;9-(2-Methoxyphenyl)-8-oxo-2-pyrazol-4-yl-7-hydropurine-6-carboxamide;9-(2-Methoxyphenyl)-8-oxo-2-pyrazol-3-yl-7-hydropurine-6-carboxamide;9-(4-Aminocyclohexyl)-2-(3-hydroxyphenyl)-8-oxo-7-hydropurine-6-carboxamide;2-[3-(Difluoromethyl)phenyl]-9-(2-methoxyphenyl)-8-oxo-7-hydropurine-6-carbox-amide;2-[5-(Difluoromethyl)-2-fluorophenyl]-9-(2-methoxyphenyl)-8-oxo-7-hydropurine-6-carboxamide;2-(1H-benzo[d]imidazol-4-yl)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;2-(6-Hydroxypyridin-3-yl)-8-oxo-9-(2-(trifluoromethyl)phenyl)-8,9-dihydro-7H-purine-6-carboxamide;2-(1H-benzo[d]imidazol-6-yl)-9-(2-fluorophenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;2-Benzimidazol-6-yl-8-oxo-9-[2-(trifluoromethyl)phenyl]-7-hydropurine-6-carboxamide;2-(5-Chloropyridin-3-yl)-8-oxo-9-(2-(trifluoromethyl)phenyl)-8,9-dihydro-7H-purine-6-carboxamide;trans-4-(6-Carbamoyl-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purin-2-ylamino)cyclohexyl carbamate;(R)-9-(2-Methoxyphenyl)-8-oxo-2-(pyrrolidin-3-ylamino)-8,9-dihydro-7H-purine-6-carboxamide;(S)-9-(2-Methoxyphenyl)-8-oxo-2-(pyrrolidin-3-ylamino)-8,9-dihydro-7H-purine-6-carboxamide;(cis)-4-(6-Carbamoyl-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purin-2-ylamino)cyclohexyl carbamate;2-(trans-4-Hydroxycyclohexylamino)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;2-(4-Chloropyridin-3-yl)-8-oxo-9-(2-(trifluoromethyl)phenyl)-8,9-dihydro-7H-purine-6-carboxamide;2-(cis-4-Hydroxycyclohexylamino)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;2-(4-((1H-Imidazol-1-yl)methyl)phenylamino)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;2-(4-Hydroxypyridin-3-yl)-8-oxo-9-(2-(trifluoromethyl)phenyl)-8,9-dihydro-7H-purine-6-carboxamide;(R)-9-(2-Methoxyphenyl)-8-oxo-2-(pyrrolidin-2-ylmethylamino)-8,9-dihydro-7H-purine-6-carboxamide;(S)-9-(2-Methoxyphenyl)-8-oxo-2-(pyrrolidin-2-ylmethylamino)-8,9-dihydro-7H-purine-6-carboxamide;2-(4-(1H-1,2,4-Triazol-3-yl)phenyl)-9-(2-methoxyphenyl)-8-oxo-7-hydropurine-6-carboxamide;2-(2-Hydroxyethylamino)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;9-(2-Methoxyphenyl)-8-oxo-2-(2-(trifluoromethyl)-1H-benzo[d]imidazol-6-yl)-8,9-dihydro-7H-purine-6-carboxamide;2-(3-(1H-1,2,4-Triazol-3-yl)phenyl)-9-(2-methoxyphenyl)-8-oxo-7-hydropurine-6-carboxamide;9-(Biphenyl-2-yl)-2-(3-hydroxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;2-(4-(1H-1,2,4-Triazol-3-yl)phenyl)-9-(2-fluorophenyl)-8-oxo-7-hydropurine-6-carboxamide;2-(4-(1H-1,2,4-Triazol-3-yl)phenyl)-9-(2-isopropylphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;9-(2-Methoxyphenyl)-2-(2-methyl-1H-benzo[d]imidazol-6-yl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;2-(3-(Hydroxymethyl)phenylamino)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;2-(2-(Hydroxymethyl)phenylamino)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;9-(2-tert-Butylphenyl)-2-(3-hydroxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;2-(3-Hydroxyphenyl)-8-oxo-9-(2-phenoxyphenyl)-8,9-dihydro-7H-purine-6-carboxamide;2-(1H-Benzo[d]imidazol-6-yl)-9-(2-isopropylphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;2-(1H-Indazol-4-yl)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;2-(2-Hydroxypyridin-3-yl)-8-oxo-9-(2-(trifluoromethyl)phenyl)-8,9-dihydro-7H-purine-6-carboxamide;2-(1H-Imidazo[4,5-b]pyridin-6-yl)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;2-(4-(1H-Imidazol-1-yl)phenyl)-9-(2-isopropylphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;9-(2-Cyclohexylphenyl)-2-(3-hydroxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;2-(4-(1H-Imidazol-2-yl)phenyl)-9-(2-isopropylphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;2-(1H-Benzo[d]imidazol-1-yl)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;2-(1H-Imidazo[4,5-b]pyridin-6-yl)-9-(2-isopropylphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;9-(2-Isopropylphenyl)-8-oxo-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)-8,9-dihydro-7H-purine-6-carboxamide;2-(1H-Imidazo[4,5-b]pyridin-6-yl)-8-oxo-9-(2-(trifluoromethyl)phenyl)-8,9-dihydro-7H-purine-6-carboxamide;9-(2-Methoxyphenyl)-2-(2-(methylthio)-1H-benzo[d]imidazol-5-yl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;2-(1H-Indol-5-yl)-9-(2-isopropylphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;9-(Cyclohexylmethyl)-2-(3-hydroxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;9-(2,3-Dihydro-1H-inden-1-yl)-2-(3-hydroxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;2-(3-Hydroxyphenyl)-9-isobutyl-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;9-(trans-4-Methoxycyclohexyl)-2-(3-hydroxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;9-(cis-4-Methoxycyclohexyl)-2-(3-hydroxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;2-(3-Hydroxyphenyl)-8-oxo-9-(5,6,7,8-tetrahydronaphthalen-1-yl)-8,9-dihydro-7H-purine-6-carboxamide;2-(4-(1H-1,2,4-Triazol-3-yl)phenyl)-9-cyclohexyl-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;2-(3-Hydroxyphenyl)-9-(1H-indol-4-yl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;9-(2-Fluoro-3-methoxyphenyl)-2-(3-hydroxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;9-(2-Fluoro-5-methoxyphenyl)-2-(3-hydroxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;9-Cyclohexyl-2-(1H-imidazo[4,5-b]pyridin-6-yl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;2-(3-Hydroxyphenyl)-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purine-6-carboxamide;2-(3-Hydroxyphenyl)-8-oxo-9-((tetrahydro-2H-pyran-4-yl)methyl)-8,9-dihydro-7H-purine-6-carboxamide;9-(2-Cyclopentylphenyl)-2-(3-hydroxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;2-(3-Hydroxyphenyl)-8-oxo-9-(piperidin-4-yl)-8,9-dihydro-7H-purine-6-carboxamide;9-(2-Fluoro-4-methoxyphenyl)-2-(3-hydroxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;2-(1H-benzo[d]imidazol-6-yl)-9-cyclohexyl-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;2-Benzimidazol-6-yl-9-(trans-4-methoxycyclohexyl)-8-oxo-7-hydropurine-6-carboxamide;2-(4-(Aminomethyl)phenyl)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;2-(3-Hydroxyphenyl)-9-(cis-4-(methoxymethyl)cyclohexyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;9-(trans-4-Aminocyclohexyl)-2-(3-hydroxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;2-(3-Hydroxyphenyl)-9-(2-isobutylphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;(R)-2-(3-Hydroxyphenyl)-8-oxo-9-(tetrahydrofuran-3-yl)-8,9-dihydro-7H-purine-6-carboxamide;(S)-2-(3-Hydroxyphenyl)-8-oxo-9-(tetrahydrofuran-3-yl)-8,9-dihydro-7H-purine-6-carboxamide;2-(3-(Aminomethyl)phenyl)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;2-(4-(1H-1,2,3-Triazol-5-yl)phenyl)-9-(2-isopropylphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;2-(4-(1H-1,2,4-Triazol-3-yl)phenyl)-9-(cis-4-methoxycyclohexyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;2-(1H-Benzo[d]imidazol-6-yl)-9-(cis-4-methoxycyclohexyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;2-(1H-Imidazo[4,5-b]pyridin-6-yl)-9-(cis-4-methoxycyclohexyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;2-(3-Hydroxyphenyl)-9-((1r,4r)-4-(methoxymethyl)cyclohexyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide; and9-(2-Isopropylphenyl)-2-(4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide, and pharmaceutically acceptable salts, clathrates,solvates, stereoisomers, tautomers, and prodrugs thereof.

In one embodiment, the TOR kinase inhibitors include compounds havingthe following formula (III):

and pharmaceutically acceptable salts, clathrates, solvates,stereoisomers, tautomers, and prodrugs thereof, wherein:

R¹ is substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted aryl, substituted or unsubstituted cycloalkyl, substitutedor unsubstituted heterocyclyl, or substituted or unsubstitutedheterocyclylalkyl;

R² is H, substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted heterocyclylalkyl, substituted orunsubstituted aralkyl, or substituted or unsubstituted cycloalkylalkyl;

R³ and R⁴ are each independently H, substituted or unsubstituted C₁₋₈alkyl, substituted or unsubstituted aryl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted heterocyclylalkyl, substituted or unsubstituted aralkyl,substituted or unsubstituted cycloalkylalkyl, or R³ and R⁴, togetherwith the atoms to which they are attached, form a substituted orunsubstituted cycloalkyl or substituted or unsubstituted heterocyclyl;

or R² and one of R³ and R⁴, together with the atoms to which they areattached, form a substituted or unsubstituted heterocyclyl,

wherein in certain embodiments, the TOR kinase inhibitors do not includethe compounds depicted below, namely:

-   6-(4-hydroxyphenyl)-4-(3-methoxybenzyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;

-   6-(4-(1H-1,2,4-triazol-5-yl)phenyl)-3-(cyclohexylmethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;    or,

-   (R)-6-(4-(1H-1,2,4-triazol-5-yl)phenyl)-3-(cyclohexylmethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one.

In some embodiments of compounds of formula (III), R¹ is substituted orunsubstituted aryl or substituted or unsubstituted heteroaryl. In oneembodiment, R¹ is phenyl, pyridyl, pyrimidyl, benzimidazolyl, indolyl,indazolyl, 1H-pyrrolo[2,3-b]pyridyl, 1H-imidazo[4,5-b]pyridyl,1H-imidazo[4,5-b]pyridin-2(3H)-onyl, 3H-imidazo[4,5-b]pyridyl, orpyrazolyl, each optionally substituted. In some embodiments, R¹ isphenyl substituted with one or more substituents independently selectedfrom the group consisting of substituted or unsubstituted C₁₋₈ alkyl(for example, methyl), substituted or unsubstituted heterocyclyl (forexample, substituted or unsubstituted triazolyl or pyrazolyl), halogen(for example, fluorine), aminocarbonyl, cyano, hydroxyalkyl (forexample, hydroxypropyl), and hydroxy. In other embodiments, R¹ ispyridyl substituted with one or more substituents independently selectedfrom the group consisting of substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted heterocyclyl (for example, substituted orunsubstituted triazolyl), halogen, aminocarbonyl, cyano, hydroxyalkyl,—OR, and —NR₂, wherein each R is independently H, or a substituted orunsubstituted C₁₋₄ alkyl. In yet other embodiments, R¹ is1H-pyrrolo[2,3-b]pyridyl or benzimidazolyl, each optionally substitutedwith one or more substituents independently selected from the groupconsisting of substituted or unsubstituted C₁₋₈ alkyl, and —NR₂, whereineach R is independently H, or a substituted or unsubstituted C₁₋₄ alkyl.

In some embodiments of compounds of formula (III), R¹ is

wherein R is at each occurrence independently H, or a substituted orunsubstituted C₁₋₄ alkyl (for example, methyl); R′ is at each occurrenceindependently a substituted or unsubstituted C₁₋₄ alkyl, halogen (forexample, fluorine), cyano, —OR, or —NR₂; m is 0-3; and n is 0-3. It willbe understood by those skilled in the art that any of the substitutentsR′ may be attached to any suitable atom of any of the rings in the fusedring systems. It will also be understood by those skilled in the artthat the connecting bond of R¹ (designated by the bisecting wavy line)may be attached to any of the atoms in any of the rings in the fusedring systems.

In some embodiments of compounds of formula (III), R¹ is

wherein R is at each occurrence independently H, or a substituted orunsubstituted C₁₋₄ alkyl; R′ is at each occurrence independently asubstituted or unsubstituted C₁₋₄ alkyl, halogen, cyano, —OR, or —NR₂; mis 0-3; and n is 0-3.

In some embodiments of compounds of formula (III), R² is H, substitutedor unsubstituted C₁₋₈ alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedC₁₋₄ alkyl-heterocyclyl, substituted or unsubstituted C₁₋₄ alkyl-aryl,or substituted or unsubstituted C₁₋₄ alkyl-cycloalkyl. For example, R²is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl,tert-butyl, n-pentyl, isopentyl, cyclopentyl, cyclohexyl,tetrahydrofuranyl, tetrahydropyranyl, (C₁₋₄ alkyl)-phenyl, (C₁₋₄alkyl)-cyclopropyl, (C₁₋₄ alkyl)-cyclobutyl, (C₁₋₄ alkyl)-cyclopentyl,(C₁₋₄ alkyl)-cyclohexyl, (C₁₋₄ alkyl)-pyrrolidyl, (C₁₋₄alkyl)-piperidyl, (C₁₋₄ alkyl)-piperazinyl, (C₁₋₄ alkyl)-morpholinyl,(C₁₋₄ alkyl)-tetrahydrofuranyl, or (C₁₋₄ alkyl)-tetrahydropyranyl, eachoptionally substituted.

In other embodiments, R² is H, C₁₋₄ alkyl, (C₁₋₄alkyl)OR),

wherein R is at each occurrence independently H, or a substituted orunsubstituted C₁₋₄ alkyl (for example, methyl); R′ is at each occurrenceindependently H, —OR, cyano, or a substituted or unsubstituted C₁₋₄alkyl (for example, methyl); and p is 0-3.

In some such embodiments, R² is H, C₁₋₄ alkyl, (C₁₋₄alkyl)(OR),

wherein R is at each occurrence independently H, or a substituted orunsubstituted C₁₋₂ alkyl; R′ is at each occurrence independently H, —OR,cyano, or a substituted or unsubstituted C₁₋₂ alkyl; and p is 0-1.

In some other embodiments of compounds of formula (III), R² and one ofR³ and R⁴ together with the atoms to which they are attached form asubstituted or unsubstituted heterocyclyl. For example, in someembodiments, the compound of formula (III) is

wherein R is at each occurrence independently H, or a substituted orunsubstituted C₁₋₄ alkyl; R″ is H, OR, or a substituted or unsubstitutedC₁₋₄ alkyl; and R¹ is as defined herein.

In some embodiments of compounds of formula (III), R³ and R⁴ are both H.In others, one of R³ and R⁴ is H and the other is other than H. In stillothers, one of R³ and R⁴ is C₁₋₄ alkyl (for example, methyl) and theother is H. In still others, both of R³ and R⁴ are C₁₋₄ alkyl (forexample, methyl).

In some such embodiments described above, R¹ is substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl. Forexample, R¹ is phenyl, pyridyl, pyrimidyl, benzimidazolyl, indolyl,indazolyl, 1H-pyrrolo[2,3-b]pyridyl, 1H-imidazo[4,5-b]pyridyl,1H-imidazo[4,5-b]pyridin-2(3H)-onyl, 3H-imidazo[4,5-b]pyridyl, orpyrazolyl, each optionally substituted. In some embodiments, R¹ isphenyl substituted with one or more substituents independently selectedfrom the group consisting of substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted heterocyclyl, halogen, aminocarbonyl,cyano, hydroxyalkyl and hydroxy. In others, R¹ is pyridyl substitutedwith one or more substituents independently selected from the groupconsisting of cyano, substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted heterocyclyl, hydroxyalkyl, halogen,aminocarbonyl, —OR, and —NR₂, wherein each R is independently H, or asubstituted or unsubstituted C₁₋₄ alkyl. In others, R¹ is1H-pyrrolo[2,3-b]pyridyl or benzimidazolyl, optionally substituted withone or more substituents independently selected from the groupconsisting of substituted or unsubstituted C₁₋₈ alkyl, and —NR₂, whereinR is independently H, or a substituted or unsubstituted C₁₋₄ alkyl

In certain embodiments, the compounds of formula (III) have an R¹ groupset forth herein and an R² group set forth herein.

In some embodiments of compounds of formula (III), the compound at aconcentration of 10 μM inhibits mTOR, DNA-PK, or PI3K or a combinationthereof, by at least about 50%. Compounds of formula (III) may be shownto be inhibitors of the kinases above in any suitable assay system.

Representative TOR kinase inhibitors of formula (III) include compoundsfrom Table C.

TABLE C6-(1H-pyrrolo[2,3-b]pyridin-3-yl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(4-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-4-((trans-4-methoxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-4-((cis-4-methoxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-((trans-4-methoxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-4-((trans-4-hydroxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-((cis-4-methoxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-((trans-4-hydroxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-(cis-4-hydroxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-((cis-4-hydroxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-4-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-(trans-4-hydroxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-4-((cis-4-hydroxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-(cis-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-isopropyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-4-(cis-4-hydroxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-4-(cis-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-4-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-ethyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-4-(trans-4-hydroxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-4-isopropyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;4-ethyl-6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(3-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(3-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-4-(cis-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(3-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-4-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;4-(2-methoxyethyl)-6-(4-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(3-(1H-1,2,4-triazol-5-yl)phenyl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;5-(8-(2-methoxyethyl)-6-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)-4-methylpicolinamide;3-(6-oxo-8-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)benzamide;3-(6-oxo-8-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)benzonitrile;5-(8-(trans-4-methoxycyclohexyl)-6-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)-4-methylpicolinamide;6-(1H-imidazo[4,5-b]pyridin-6-yl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(1H-indazol-6-yl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;4-((1R,3S)-3-methoxycyclopentyl)-6-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;4-((1S,3R)-3-methoxycyclopentyl)-6-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;4-((1R,3R)-3-methoxycyclopentyl)-6-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;4-((1S,3S)-3-methoxycyclopentyl)-6-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;4-ethyl-6-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(1H-pyrrolo[2,3-b]pyridin-5-yl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(1H-indol-6-yl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(1H-indol-5-yl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;4-(((1R,3S)-3-methoxycyclopentyl)methyl)-6-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;4-(((1S,3R)-3-methoxycyclopentyl)methyl)-6-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(3-fluoro-2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(3-fluoro-2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-4-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;3,3-dimethyl-6-(4-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-((1R,3S)-3-methoxycyclopentyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-((1S,3R)-3-methoxycyclopentyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(((1S,3S)-3-methoxycyclopentyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(((1R,3R)-3-methoxycyclopentyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-((1S,3S)-3-methoxycyclopentyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-((1R,3R)-3-methoxycyclopentyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(((1R,3S)-3-methoxycyclopentyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(((1S,3R)-3-methoxycyclopentyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(3-fluoro-4-(4H-1,2,4-triazol-3-yl)phenyl)-4-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(3-fluoro-4-(4H-1,2,4-triazol-3-yl)phenyl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7′-(2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-1′-((tetrahydro-2H-pyran-4-yl)methyl)-1′H-spiro[cyclopentane-1,2′-pyrazino[2,3-b]pyrazin]-3′(4′H)-one;7′-(2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-1′-((tetrahydro-2H-pyran-4-yl)methyl)-1′H-spiro[cyclobutane-1,2′-pyrazino[2,3-b]pyrazin]-3′(4′H)-one;4-(cyclopropylmethyl)-6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7′-(2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-1′H-spiro[cyclopentane-1,2′-pyrazino[2,3-b]pyrazin]-3′(4′H)-one;7′-(2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-1′H-spiro[cyclobutane-1,2′-pyrazino[2,3-b]pyrazin]-3′(4′H)-one;7′-(2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-1′H-spiro[cyclopropane-1,2′-pyrazino[2,3-b]pyrazin]-3′(4′H)-one;(R)-6-(4-(4H-1,2,4-triazol-3-yl)phenyl)-4-((tetrahydrofuran-2-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;(S)-6-(4-(4H-1,2,4-triazol-3-yl)phenyl)-4-((tetrahydrofuran-2-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(1H-indazol-5-yl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;4-(6-oxo-8-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)benzamide;4-(2-methoxyethyl)-3,3-dimethyl-6-(2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;4-ethyl-3,3-dimethyl-6-(2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;3,3-dimethyl-6-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;(R)-6-(6-(1-hydroxyethyl)pyridin-3-yl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;3,3-dimethyl-6-(2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-4-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(6-(2-hydroxypropan-2-yl)-4-methylpyridin-3-yl)-4-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(6-(2-hydroxypropan-2-yl)-4-methylpyridin-3-yl)-4-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;3,3-dimethyl-6-(2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;3,3-dimethyl-6-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(6-(2-hydroxypropan-2-yl)-2-methylpyridin-3-yl)-4-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(6-(2-hydroxypropan-2-yl)-2-methylpyridin-3-yl)-4-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;(S)-6-(6-(1-hydroxyethyl)pyridin-3-yl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;3,3-dimethyl-6-(2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,3-dimethyl-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(4-(2-hydroxypropan-2-yl)phenyl)-4-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(4-(2-hydroxypropan-2-yl)phenyl)-4-((trans-4-methoxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;4-(cis-4-methoxycyclohexyl)-6-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;4-(trans-4-methoxycyclohexyl)-6-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(4-(2-hydroxypropan-2-yl)phenyl)-4-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;4-(2-methoxyethyl)-6-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;9-(6-(4H-1,2,4-triazol-3-yl)-3-pyridyl)-6,11,4a-trihydromorpholino[4,3-e]pyrazino[2,3-b]pyrazin-5-one;6-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;5-(8-(cis-4-methoxycyclohexyl)-6-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)-6-methylpicolinonitrile;6-(6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;9-(4-(4H-1,2,4-triazol-3-yl)-2-methylphenyl)-3-(2-methoxyacetyl)-6,11,4a-trihydropiperazino[1,2-e]pyrazino[2,3-b]pyrazin-5-one;9-(4-(4H-1,2,4-triazol-3-yl)-2-methylphenyl)-6,11,4a-trihydropiperazino[1,2-e]pyrazino[2,3-b]pyrazin-5-one;9-(4-(4H-1,2,4-triazol-3-yl)-2-methylphenyl)-3-(2-methoxyethyl)-6,11,4a-trihydropiperazino[1,2-e]pyrazino[2,3-b]pyrazin-5-one;4-(cyclopentylmethyl)-6-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;9-(6-(4H-1,2,4-triazol-3-yl)-2-methyl-3-pyridyl)-6,11,4a-trihydromorpholino[4,3-e]pyrazino[2,3-b]pyrazin-5-one;4-(trans-4-hydroxycyclohexyl)-6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;4-(cis-4-hydroxycyclohexyl)-6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-((tetrahydrofuran-3-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;4-(cyclopentylmethyl)-6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-neopentyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-isobutyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;3-methyl-6-(2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(piperidin-4-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(2-(tetrahydro-2H-pyran-3-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;8-(4-(4H-1,2,4-triazol-3-yl)-2-methylphenyl)(3aS,2R)-2-methoxy-5,10,3a-trihydropyrazino[2,3-b]pyrrolidino[1,2-e]pyrazin-4-one;8-(4-(4H-1,2,4-triazol-3-yl)-2-methylphenyl)(2R,3aR)-2-methoxy-5,10,3a-trihydropyrazino[2,3-b]pyrrolidino[1,2-e]pyrazin-4-one;8-(4-(4H-1,2,4-triazol-3-yl)-2-methylphenyl)(2S,3aR)-2-methoxy-5,10,3a-trihydropyrazino[2,3-b]pyrrolidino[1,2-e]pyrazin-4-one;8-(4-(4H-1,2,4-triazol-3-yl)-2-methylphenyl)(2S,3aS)-2-methoxy-5,10,3a-trihydropyrazino[2,3-b]pyrrolidino[1,2-e]pyrazin-4-one;6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(3-methoxypropyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;(S)-6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-((tetrahydrofuran-2-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;(R)-6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-((tetrahydrofuran-2-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;9-(4-(4H-1,2,4-triazol-3-yl)-2-methylphenyl)-3-methyl-6,11,4a-trihydropiperazino[1,2-e]pyrazino[2,3-b]pyrazin-5-one;9-(4-(4H-1,2,4-triazol-3-yl)phenyl)-6,11,4a-trihydromorpholino[4,3-e]pyrazino[2,3-b]pyrazin-5-one;9-(4-(4H-1,2,4-triazol-3-yl)-2-methylphenyl)-6,11,4a-trihydropiperidino[1,2-e]pyrazino[2,3-b]pyrazin-5-one;6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(cis-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(2-morpholinoethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-phenethyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;4-(cyclohexylmethyl)-6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-((trans-4-methoxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-((cis-4-methoxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;(R)-6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(tetrahydrofuran-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;(S)-6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(tetrahydrofuran-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-phenyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;(S)-6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3-methyl-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;9-[6-(1-hydroxy-isopropyl)-3-pyridyl]-6,11,4a-trihydromorpholino[4,3-e]pyrazino[2,3-b]pyrazin-5-one;6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(2-amino-7-methyl-1H-benzo[d]imidazol-5-yl)-4-(3-(trifluoromethyl)benzyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(3-(trifluoromethyl)benzyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;9-(4-(4H-1,2,4-triazol-3-yl)-2-methylphenyl)-6,11,4a-trihydromorpholino[4,3-e]pyrazino[2,3-b]pyrazin-5-one;6-(4-methyl-2-(methylamino)-1H-benzo[d]imidazol-6-yl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;8-(4-(4H-1,2,4-triazol-3-yl)-2-methylphenyl)-5,10,3a-trihydropyrazino[2,3-b]pyrrolidino[1,2-e]pyrazin-4-one;6-(4-(4H-1,2,4-triazol-3-yl)phenyl)-4-ethyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(4-(4H-1,2,4-triazol-3-yl)phenyl)-4-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(4-(4H-1,2,4-triazol-3-yl)phenyl)-4-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(4-(4H-1,2,4-triazol-3-yl)phenyl)-4-(3-(trifluoromethyl)benzyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(4-methyl-1H-benzo[d]imidazol-6-yl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;6-(4-(2-hydroxypropan-2-yl)phenyl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; and6-(4-(1H-1,2,4-triazol-5-yl)phenyl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one, and pharmaceutically acceptablesalts, clathrates, solvates, stereoisomers, tautomers, and prodrugsthereof.

In one embodiment, the TOR kinase inhibitors include compounds havingthe following formula (IV):

and pharmaceutically acceptable salts, clathrates, solvates,stereoisomers, tautomers, and prodrugs thereof, wherein:

R¹ is substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted aryl, substituted or unsubstituted cycloalkyl, substitutedor unsubstituted heterocyclyl, or substituted or unsubstitutedheterocyclylalkyl;

R² is H, substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted heterocyclylalkyl, substituted orunsubstituted aralkyl, or substituted or unsubstituted cycloalkylalkyl;

R³ is H, or a substituted or unsubstituted C₁₋₈ alkyl,

wherein in certain embodiments, the TOR kinase inhibitors do not include7-(4-hydroxyphenyl)-1-(3-methoxybenzyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one,depicted below:

In some embodiments of compounds of formula (IV), R¹ is substituted orunsubstituted aryl or substituted or unsubstituted heteroaryl. Forexample, R¹ is phenyl, pyridyl, pyrimidyl, benzimidazolyl,1H-pyrrolo[2,3-b]pyridyl, indazolyl, indolyl, 1H-imidazo[4,5-b]pyridyl,1H-imidazo[4,5-b]pyridin-2(3H)-onyl, 3H-imidazo[4,5-b]pyridyl, orpyrazolyl, each optionally substituted. In some embodiments, R¹ isphenyl substituted with one or more substituents independently selectedfrom the group consisting of substituted or unsubstituted C₁₋₈ alkyl(for example, methyl), substituted or unsubstituted heterocyclyl (forexample, a substituted or unsubstituted triazolyl or pyrazolyl),aminocarbonyl, halogen (for example, fluorine), cyano, hydroxyalkyl andhydroxy. In other embodiments, R¹ is pyridyl substituted with one ormore substituents independently selected from the group consisting ofsubstituted or unsubstituted C₁₋₈ alkyl (for example, methyl),substituted or unsubstituted heterocyclyl (for example, a substituted orunsubstituted triazolyl), halogen, aminocarbonyl, cyano, hydroxyalkyl(for example, hydroxypropyl), —OR, and —NR₂, wherein each R isindependently H, or a substituted or unsubstituted C₁₋₄ alkyl. In someembodiments, R¹ is 1H-pyrrolo[2,3-b]pyridyl or benzimidazolyl,optionally substituted with one or more substituents independentlyselected from the group consisting of substituted or unsubstituted C₁₋₈alkyl, and —NR₂, wherein R is independently H, or a substituted orunsubstituted C₁₋₄ alkyl.

In some embodiments, R¹ is

wherein R is at each occurrence independently H, or a substituted orunsubstituted C₁₋₄ alkyl (for example, methyl); R′ is at each occurrenceindependently a substituted or unsubstituted C₁₋₄ alkyl (for example,methyl), halogen (for example, fluoro), cyano, —OR, or —NR₂; m is 0-3;and n is 0-3. It will be understood by those skilled in the art that anyof the substitutents R′ may be attached to any suitable atom of any ofthe rings in the fused ring systems.

In some embodiments of compounds of formula (IV), R¹ is

wherein R is at each occurrence independently H, or a substituted orunsubstituted C₁₋₄ alkyl; R′ is at each occurrence independently asubstituted or unsubstituted C₁₋₄ alkyl, halogen, cyano, —OR or —NR₂; mis 0-3; and n is 0-3.

In some embodiments of compounds of formula (IV), R² is H, substitutedor unsubstituted C₁₋₈ alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedC₁₋₄ alkyl-heterocyclyl, substituted or unsubstituted C₁₋₄ alkyl-aryl,or substituted or unsubstituted C₁₋₄ alkyl-cycloalkyl. For example, R²is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl,tert-butyl, n-pentyl, isopentyl, cyclopentyl, cyclohexyl,tetrahydrofuranyl, tetrahydropyranyl, (C₁₋₄ alkyl)-phenyl, (C₁₋₄alkyl)-cyclopropyl, (C₁₋₄ alkyl)-cyclobutyl, (C₁₋₄ alkyl)-cyclopentyl,(C₁₋₄ alkyl)-cyclohexyl, (C₁₋₄ alkyl)-pyrrolidyl, (C₁₋₄alkyl)-piperidyl, (C₁₋₄ alkyl)-piperazinyl, (C₁₋₄ alkyl)-morpholinyl,(C₁₋₄ alkyl)-tetrahydrofuranyl, or (C₁₋₄ alkyl)-tetrahydropyranyl, eachoptionally substituted.

In other embodiments, R² is H, C₁₋₄ alkyl, (C₁₋₄alkyl)(OR),

wherein R is at each occurrence independently H, or a substituted orunsubstituted C₁₋₄ alkyl (for example, methyl); R′ is at each occurrenceindependently H, —OR, cyano, or a substituted or unsubstituted C₁₋₄alkyl (for example, methyl); and p is 0-3.

In other embodiments of compounds of formula (IV), R² is H, C₁₋₄ alkyl,(C₁₋₄alkyl)(OR),

wherein R is at each occurrence independently H, or a substituted orunsubstituted C₁₋₂ alkyl; R′ is at each occurrence independently H, —OR,cyano, or a substituted or unsubstituted C₁₋₂ alkyl; and p is 0-1.

In other embodiments of compounds of formula (IV), R³ is H.

In some such embodiments described herein, R¹ is substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl. Forexample, R¹ is phenyl, pyridyl, pyrimidyl, benzimidazolyl,1H-pyrrolo[2,3-b]pyridyl, indazolyl, indolyl, 1H-imidazo[4,5-b]pyridine,pyridyl, 1H-imidazo[4,5-b]pyridin-2(3H)-onyl, 3H-imidazo[4,5-b]pyridyl,or pyrazolyl, each optionally substituted. In some embodiments, R¹ isphenyl substituted with one or more substituents independently selectedfrom the group consisting of substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted heterocyclyl, aminocarbonyl, halogen,cyano, hydroxyalkyl and hydroxy. In others, R¹ is pyridyl substitutedwith one or more substituents independently selected from the groupconsisting of C₁₋₈ alkyl, substituted or unsubstituted heterocyclyl,halogen, aminocarbonyl, cyano, hydroxyalkyl, —OR, and —NR₂, wherein eachR is independently H, or a substituted or unsubstituted C₁₋₄ alkyl. Instill others, R¹ is 1H-pyrrolo[2,3-b]pyridyl or benzimidazolyl,optionally substituted with one or more substituents independentlyselected from the group consisting of substituted or unsubstituted C₁₋₈alkyl, and —NR₂, wherein R is independently H, or a substituted orunsubstituted C₁₋₄ alkyl.

In certain embodiments, the compounds of formula (IV) have an R¹ groupset forth herein and an R² group set forth herein.

In some embodiments of compounds of formula (IV), the compound at aconcentration of 10 μM inhibits mTOR, DNA-PK, PI3K, or a combinationthereof by at least about 50%. Compounds of formula (IV) may be shown tobe inhibitors of the kinases above in any suitable assay system.

Representative TOR kinase inhibitors of formula (IV) include compoundsfrom Table D.

TABLE D7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-((trans-4-methoxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(cis-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-((cis-4-methoxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-ethyl-7-(1H-pyrrolo[3,2-b]pyridin-5-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-((cis-4-methoxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(1H-benzo[d]imidazol-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-((trans-4-methoxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-((trans-4-hydroxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(cis-4-hydroxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(cis-4-hydroxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-ethyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; 7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-((cis-4-hydroxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(1H-indol-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-((trans-4-hydroxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-((cis-4-hydroxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(trans-4-hydroxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-isopropyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(trans-4-hydroxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-isopropyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-ethyl-7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(2-hydroxypyridin-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-isopropyl-7-(4-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;5-(8-isopropyl-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)-4-methylpicolinamide;7-(1H-indazol-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(2-aminopyrimidin-5-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(2-aminopyridin-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(methylamino)pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-hydroxypyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(4-(1H-pyrazol-3-yl)phenyl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(1H-indazol-4-yl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(1H-indazol-6-yl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(pyrimidin-5-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-methoxypyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-(2-methoxyethyl)-7-(1H-pyrrolo[2,3-b]pyridin-5-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-ethyl-7-(1H-pyrrolo[2,3-b]pyridin-5-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-ethyl-7-(1H-indazol-4-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(pyridin-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-aminopyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-methyl-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;2-(2-hydroxypropan-2-yl)-5-(8-(trans-4-methoxycyclohexyl)-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)pyridine 1-oxide;4-methyl-5-(7-oxo-8-((tetrahydro-2H-pyran-4-yl)methyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)picolinamide;5-(8-((cis-4-methoxycyclohexyl)methyl)-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)-4-methylpicolinamide;7-(1H-pyrazol-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-(trans-4-methoxycyclohexyl)-7-(4-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;3-((7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-2-oxo-3,4-dihydropyrazino[2,3-b]pyrazin-1(2H)-yl)methyl)benzonitrile;1-((trans-4-methoxycyclohexyl)methyl)-7-(4-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;3-(7-oxo-8-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)benzamide;5-(8-((trans-4-methoxycyclohexyl)methyl)-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)-4-methylpicolinamide;3-((7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-2-oxo-3,4-dihydropyrazino[2,3-b]pyrazin-1(2H)-yl)methyl)benzonitrile;7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((1R,3R)-3-methoxycyclopentyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((1S,3R)-3-methoxycyclopentyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((1S,3S)-3-methoxycyclopentyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((1R,3S)-3-methoxycyclopentyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(1H-indazol-6-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(2-morpholinoethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-(trans-4-hydroxycyclohexyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-(cis-4-hydroxycyclohexyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(2-morpholinoethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-isopropyl-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(1H-imidazo[4,5-b]pyridin-6-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-((cis-4-methoxycyclohexyl)methyl)-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-(trans-4-hydroxycyclohexyl)-7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-(cis-4-hydroxycyclohexyl)-7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;4-(7-oxo-8-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)benzamide;7-(1H-indazol-5-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-((1S,3R)-3-methoxycyclopentyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-((1R,3R)-3-methoxycyclopentyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-((1R,3S)-3-methoxycyclopentyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-((1S,3S)-3-methoxycyclopentyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(1H-indol-5-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-ethyl-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(1H-indol-6-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(4-(2-hydroxypropan-2-yl)phenyl)-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-((trans-4-methoxycyclohexyl)methyl)-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((cis-4-methoxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-(2-methoxyethyl)-7-(4-methyl-2-(methylamino)-1H-benzo[d]imidazol-6-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(7-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-(2-methoxyethyl)-7-(4-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-benzyl-7-(2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(3-fluoro-4-(4H-1,2,4-triazol-3-yl)phenyl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(3-fluoro-4-(4H-1,2,4-triazol-3-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(3-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-(trans-4-methoxycyclohexyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(5-fluoro-2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(3-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-(2-methoxyethyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((trans-4-methoxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-(cyclopentylmethyl)-7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(4-(2-hydroxypropan-2-yl)phenyl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;(S)-7-(6-(1-hydroxyethyl)pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;(R)-7-(6-(1-hydroxyethyl)pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(4-(2-hydroxypropan-2-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(4-(trifluoromethyl)benzyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(3-(trifluoromethyl)benzyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(3-methoxypropyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(4-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(4-methyl-2-(methylamino)-1H-benzo[d]imidazol-6-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(2-amino-4-methyl-1H-benzo[d]imidazol-6-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;(R)-7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3-methyl-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;(S)-7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3-methyl-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,3-dimethyl-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(2-amino-4-methyl-1H-benzo[d]imidazol-6-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;7-(4-(1H-1,2,4-triazol-5-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;1-(1-hydroxypropan-2-yl)-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; and1-(2-hydroxyethyl)-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one, and pharmaceutically acceptablesalts, clathrates, solvates, stereoisomers, tautomers, and prodrugsthereof.

5.3 Methods for Making TOR Kinase Inhibitors

The TOR kinase inhibitors can be obtained via standard, well-knownsynthetic methodology, see e.g., March, J. Advanced Organic Chemistry;Reactions Mechanisms, and Structure, 4th ed., 1992. Starting materialsuseful for preparing compounds of formula (III) and intermediatestherefore, are commercially available or can be prepared fromcommercially available materials using known synthetic methods andreagents.

Particular methods for preparing compounds of formula (I) are disclosedin U.S. Pat. No. 7,981,893, issued Jul. 19, 2011, incorporated byreference herein in its entirety. Particular methods for preparingcompounds of formula (II) are disclosed in U.S. Pat. No. 7,968,556,issued Jun. 28, 2011, incorporated by reference herein in its entirety.Particular methods for preparing compounds of formula (III) and (IV) aredisclosed in U.S. Pat. No. 8,110,578, issued Feb. 7, 2012, and U.S.Publication No. 2011/0137028, filed Oct. 25, 2010, incorporated byreference herein in their entirety.

5.4 Methods of Use

Provided herein are methods for treating or preventing advancednon-small cell lung cancer, comprising administering an effective amountof a TOR kinase inhibitor and an effective amount of erlotinib or acytidine analog to a patient having advanced non-small cell lung cancer.In certain embodiments, the cytidine analog is oral azacitidine. Incertain embodiments, advanced non-small cell lung cancer isnon-small-cell lung carcinoma, Stage IIIB non-small cell lung cancer orStage IV non-small cell lung cancer. In certain embodiments, the patienthas failed at least one line of standard therapy. In one embodiment thestandard therapy is chemotherapy or treatment with an EGFR inhibitor,for example, erlotinib. In one embodiment, the advanced non-small celllung cancer is EGFR inhibitor resistant, for example, erlotinibresistant. In one such embodiment, the advanced non-small cell lungcancer is characterized by a EGFR inhibitor resistant mutation, forexample, T790M EGFR mutation. In another embodiment, the advancednon-small cell lung cancer has an EGFR activating mutation, for example,L858R EGFR mutation. In some embodiments, the methods further comprisescreening the patient's non-small cell lung cancer for an EGFR inhibitorresistant mutation, for example, an erlotinib resistant mutation. Inanother the methods further comprise screening the patient's non-smallcell lung cancer for an EGFR activating mutation.

Also provided are methods for predicting therapeutic efficacy oftreatment of a patient having advanced non-small cell lung cancer with aTOR kinase inhibitor in combination with erlotinib or a cytidine analog,comprising obtaining a biological sample of the patient's cancer, andscreening said patient's cancer for the presence of an EGFR mutation,wherein the presence of an mutation is predictive of therapeuticefficacy of treatment with the TOR kinase inhibitor in combination witherlotinib or a cytidine analog. In one such embodiment, the mutation isan activating mutation. In another, the mutation results in EGFRinhibitor resistance. As is well known in the art, screening for an EGFRmutation can be performed by, for example, EGFR gene sequencing.

In certain embodiments, provided herein are methods for achieving aResponse Evaluation Criteria in Solid Tumors (for example, RECIST 1.1)of complete response, partial response or stable disease, comprisingadministering an effective amount of a TOR kinase inhibitor incombination with an effective amount of erlotinib or a cytidine analogto a patient having advanced non-small cell lung cancer. In certainembodiments, the cytidine analog is oral azacitidine.

In certain embodiments, provided herein are methods for increasingsurvival without tumor progression of a patient having advancednon-small cell lung cancer, comprising administering an effective amountof a TOR kinase inhibitor in combination with an effective amount oferlotinib or a cytidine analog to said patient. In certain embodiments,the cytidine analog is oral azacitidine.

In one embodiment, provided herein are methods for preventing ordelaying a Response Evaluation Criteria in Solid Tumors (for example,RECIST 1.1) of progressive disease in a patient, comprisingadministering an effective amount of a TOR kinase inhibitor incombination with an effective amount of erlotinib or a cytidine analogto a patient having advanced non-small cell lung cancer. In certainembodiments, the cytidine analog is oral azacitidine. In one embodimentthe prevention or delaying of progressive disease is characterized orachieved by a change in overall size of the target lesions, of forexample, between −30% and +20% compared to pre-treatment. In anotherembodiment, the change in size of the target lesions is a reduction inoverall size of more than 30%, for example, more than 50% reduction intarget lesion size compared to pre-treatment. In another, the preventionis characterized or achieved by a reduction in size or a delay inprogression of non-target lesions compared to pre-treatment. In oneembodiment, the prevention is achieved or characterized by a reductionin the number of target lesions compared to pre-treatment. In another,the prevention is achieved or characterized by a reduction in the numberor quality of non-target lesions compared to pre-treatment. In oneembodiment, the prevention is achieved or characterized by the absenceor the disappearance of target lesions compared to pre-treatment. Inanother, the prevention is achieved or characterized by the absence orthe disappearance of non-target lesions compared to pre-treatment. Inanother embodiment, the prevention is achieved or characterized by theprevention of new lesions compared to pre-treatment. In yet anotherembodiment, the prevention is achieved or characterized by theprevention of clinical signs or symptoms of disease progression comparedto pre-treatment, such as cancer-related cachexia or increased pain.

In certain embodiments, provided herein are methods for decreasing thesize of target lesions in a patient compared to pre-treatment,comprising administering an effective amount of a TOR kinase inhibitorin combination with an effective amount of erlotinib or a cytidineanalog to a patient having advanced non-small cell lung cancer. Incertain embodiments, the cytidine analog is oral azacitidine.

In certain embodiments, provided herein are methods for decreasing thesize of a non-target lesion in a patient compared to pre-treatment,comprising administering an effective amount of a TOR kinase inhibitorin combination with an effective amount of erlotinib or a cytidineanalog to a patient having advanced non-small cell lung cancer. Incertain embodiments, the cytidine analog is oral azacitidine.

In certain embodiments, provided herein are methods for achieving areduction in the number of target lesions in a patient compared topre-treatment, comprising administering an effective amount of a TORkinase inhibitor in combination with an effective amount of erlotinib ora cytidine analog to a patient having advanced non-small cell lungcancer. In certain embodiments, the cytidine analog is oral azacitidine.

In certain embodiments, provided herein are methods for achieving areduction in the number of non-target lesions in a patient compared topre-treatment, comprising administering an effective amount of a TORkinase inhibitor in combination with an effective amount of erlotinib ora cytidine analog to a patient having advanced non-small cell lungcancer. In certain embodiments, the cytidine analog is oral azacitidine.

In certain embodiments, provided herein are methods for achieving anabsence of all target lesions in a patient, comprising administering aneffective amount of a TOR kinase inhibitor in combination with aneffective amount of erlotinib or a cytidine analog to a patient havingadvanced non-small cell lung cancer. In certain embodiments, thecytidine analog is oral azacitidine.

In certain embodiments, provided herein are methods for achieving anabsence of all non-target lesions in a patient, comprising administeringan effective amount of a TOR kinase inhibitor in combination with aneffective amount of erlotinib or a cytidine analog to a patient havingadvanced non-small cell lung cancer. In certain embodiments, thecytidine analog is oral azacitidine.

In certain embodiments, provided herein are methods for treatingnon-small cell lung cancer, the methods comprising administering aneffective amount of a TOR kinase inhibitor in combination with aneffective amount of erlotinib or a cytidine analog to a patient havingadvanced non-small cell lung cancer, wherein the treatment results in acomplete response, partial response or stable disease, as determined byResponse Evaluation Criteria in Solid Tumors (for example, RECIST 1.1).

In certain embodiments, provided herein are methods for treatingnon-small cell lung cancer, the methods comprising administering aneffective amount of a TOR kinase inhibitor in combination with aneffective amount of erlotinib or a cytidine analog to a patient havingadvanced non-small cell lung cancer, wherein the treatment results in areduction in target lesion size, a reduction in non-target lesion sizeand/or the absence of new target and/or non-target lesions, compared topre-treatment.

In certain embodiments, provided herein are methods for treatingnon-small cell lung cancer, the methods comprising administering aneffective amount of a TOR kinase inhibitor in combination with aneffective amount of erlotinib or a cytidine analog to a patient havingadvanced non-small cell lung cancer, wherein the treatment results inprevention or retarding of clinical progression, such as cancer-relatedcachexia or increased pain.

In some embodiments, provided herein are methods for treating non-smallcell lung cancer, the methods comprising administering an effectiveamount of a TOR kinase inhibitor in combination with an effective amountof erlotinib or a cytidine analog to a patient having advanced non-smallcell lung cancer, wherein the treatment results in one or more ofinhibition of disease progression, inhibition of tumor growth, reductionof primary tumor, relief of tumor-related symptoms, inhibition of tumorsecreted factors (including tumor secreted hormones, such as those thatcontribute to carcinoid syndrome), delayed appearance of primary orsecondary tumors, slowed development of primary or secondary tumors,decreased occurrence of primary or secondary tumors, slowed or decreasedseverity of secondary effects of disease, arrested tumor growth andregression of tumors, increased Time To Progression (TTP), increasedProgression Free Survival (PFS), and/or increased Overall Survival (OS),among others.

In some embodiments, the TOR kinase inhibitor is a compound as describedherein. In one embodiment, the TOR kinase inhibitor is Compound 1 (a TORkinase inhibitor set forth herein having molecular formula C₂₁H₂₇N₅O₃).In one embodiment, Compound 1 is7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((1r,4r)-4-methoxycyclohexyl)-3,4-dihydropyrazino-[2,3-b]pyrazin-2(1H)-one.

A TOR kinase inhibitor administered in combination with erlotinib or acytidine analog can be further combined with radiation therapy orsurgery. In certain embodiments, a TOR kinase inhibitor is administeredin combination with erlotinib or a cytidine analog to patient who isundergoing radiation therapy, has previously undergone radiation therapyor will be undergoing radiation therapy. In certain embodiments, a TORkinase inhibitor is administered in combination with erlotinib or acytidine analog to a patient who has undergone surgery, such as tumorremoval surgery. In certain embodiments, the cytidine analog is oralazacitidine.

Further provided herein are methods for treating patients who have beenpreviously treated for advanced non-small cell lung cancer, as well asthose who have not previously been treated. Further provided herein aremethods for treating patients who have undergone surgery in an attemptto treat advanced non-small cell lung cancer, as well as those who havenot. Because patients with advanced non-small cell lung cancer haveheterogenous clinical manifestations and varying clinical outcomes, thetreatment given to a patient may vary, depending on his/her prognosis.The skilled clinician will be able to readily determine without undueexperimentation specific secondary agents, types of surgery, and typesof non-drug based standard therapy that can be effectively used to treatan individual patient with advanced non-small cell lung cancer.

In certain embodiments, a TOR kinase inhibitor is administered incombination with a cytidine analog or erlotinib to a patient in cycles.Cycling therapy involves the administration of an active agent for aperiod of time, followed by a rest for a period of time, and repeatingthis sequential administration. Cycling therapy can reduce thedevelopment of resistance, avoid or reduce the side effects, and/orimproves the efficacy of the treatment.

In one embodiment, a TOR kinase inhibitor is administered in combinationwith a cytidine analog or erlotinib daily in single or divided doses forabout 3 days, about 5 days, about one week, about two weeks, about threeweeks, about four weeks (e.g., 28 days), about five weeks, about sixweeks, about seven weeks, about eight weeks, about ten weeks, aboutfifteen weeks, or about twenty weeks, followed by a rest period of about1 day to about ten weeks. In one embodiment, the methods provided hereincontemplate cycling treatments of about one week, about two weeks, aboutthree weeks, about four weeks, about five weeks, about six weeks, abouteight weeks, about ten weeks, about fifteen weeks, or about twentyweeks. In some embodiments, a TOR kinase inhibitor is administered incombination with a cytidine analog or erlotinib in single or divideddoses for about 3 days, about 5 days, about one week, about two weeks,about three weeks, about four weeks (e.g., 28 days), about five weeks,or about six weeks with a rest period of about 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 29, or 30 days. In someembodiments, the rest period is 1 day. In some embodiments, the restperiod is 3 days. In some embodiments, the rest period is 7 days. Insome embodiments, the rest period is 14 days. In some embodiments, therest period is 28 days. The frequency, number and length of dosingcycles can be increased or decreased.

In one embodiment, the methods provided herein comprise: i)administering to the subject a first daily dose of a TOR kinaseinhibitor in combination with a cytidine analog or erlotinib; ii)optionally resting for a period of at least one day where a cytidineanalog or erlotinib is not administered to the subject; iii)administering a second dose of a TOR kinase inhibitor in combinationwith a cytidine analog or erlotinib to the subject; and iv) repeatingsteps ii) to iii) a plurality of times.

In one embodiment, the methods provided herein comprise administering tothe subject a dose of a cytidine analog or erlotinib on day 1, followedby administering a TOR kinase inhibitor in combination with a cytidineanalog or erlotinib to the subject on day 2 and subsequent days.

In certain embodiments, a TOR kinase inhibitor in combination with acytidine analog or erlotinib is administered continuously for betweenabout 1 and about 52 weeks. In certain embodiments, a TOR kinaseinhibitor in combination with a cytidine analog or erlotinib isadministered continuously for about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, or 12 months. In certain embodiments, a TOR kinase inhibitor incombination with a cytidine analog or erlotinib is administeredcontinuously for about 7, about 14, about 21, about 28, about 35, about42, about 84, or about 112 days.

In certain embodiments, when a TOR kinase inhibitor is administered incombination with a cytidine analog, the TOR kinase inhibitor isadministered continuously for 28 days, while a cytidine analog isadministered continuously for 21 days followed by 7 days withoutadministration of a cytidine analog. In one embodiment, in a 28 daycycle, the cytidine analog is administered alone on Day 1, the cytidineanalog and the TOR kinase inhibitor are administered in combination onDays 2-21 and the TOR kinase inhibitor is administered alone on Days22-28. In some such embodiments, starting with Cycle 2 both the cytidineanalog and the TOR kinase inhibitor are administered on Day 1, thecytidine analog is continued through Day 21, while the TOR kinaseinhibitor is continued through Day 28. The 28 day cycles, as describedabove, can be continued for as long needed, such as for 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11 or 12 months or longer.

In certain embodiments, when a TOR kinase inhibitor is administered incombination with a cytidine analog, in a 28 day cycle, the cytidineanalog is administered alone on Days 1-7 and the TOR kinase inhibitor isadministered alone on Days 8-28. Such 28 day cycles can be continued foras long needed, such as for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12months or longer.

In certain embodiments, when a TOR kinase inhibitor is administered incombination with a cytidine analog, the TOR kinase inhibitor isadministered at an amount of about 5 mg to about 50 mg (such as about 10mg, about 15 mg, about 30 mg or about 45 mg) and a cytidine analog isadministered at an amount of about 50 mg to about 350 mg (such as about100 mg, about 200 mg or about 300 mg). In certain embodiments, about 10mg of a TOR kinase inhibitor is administered in combination with about100 mg, about 200 mg or about 300 mg of a cytidine analog. In certainembodiments, about 15 mg of a TOR kinase inhibitor is administered incombination with about 100 mg, about 200 mg or about 300 mg of acytidine analog. In certain embodiments, about 30 mg of a TOR kinaseinhibitor is administered in combination with about 100 mg, about 200 mgor about 300 mg of a cytidine analog. In certain embodiments, about 45mg of a TOR kinase inhibitor is administered in combination with about100 mg, about 200 mg or about 300 mg of a cytidine analog.

In certain embodiments, when a TOR kinase inhibitor is administered incombination with a cytidine analog, the TOR kinase inhibitor:cytidineanalog ratio is from about 1:1 to about 1:10. In certain embodiments,when a TOR kinase inhibitor is administered in combination with acytidine analog, the TOR kinase inhibitor:cytidine analog ratio is lessthan about 1:1, less than about 1:3 or less than about 1:10. In certainembodiments, when a TOR kinase inhibitor is administered in combinationwith a cytidine analog, the TOR kinase inhibitor:cytidine analog ratiois about 1:1, about 1:3 or about 1:10.

In certain embodiments, when a TOR kinase inhibitor is administered incombination with erlotinib, the TOR kinase inhibitor is administered atan amount of about mg to about 50 mg (such as about 10 mg, about 15 mg,about 30 mg or about 45 mg) and erlotinib is administered at an amountof about 50 mg to about 200 mg (such as about 75 mg, about 100 mg orabout 150 mg). In certain embodiments, about 10 mg of a TOR kinaseinhibitor is administered in combination with about 75 mg, about 100 mgor about 150 mg of erlotinib. In certain embodiments, about 15 mg of aTOR kinase inhibitor is administered in combination with about 75 mg,about 100 mg or about 150 mg of erlotinib. In certain embodiments, about30 mg of a TOR kinase inhibitor is administered in combination withabout 75 mg, about 100 mg or about 150 mg of erlotinib. In certainembodiments, about 45 mg of a TOR kinase inhibitor is administered incombination with about 75 mg, about 100 mg or about 150 mg of erlotinib.

In certain embodiments, when a TOR kinase inhibitor is administered incombination with erlotinib, the TOR kinase inhibitor:erlotinib ratio isfrom about 1:1 to about 1:30. In certain embodiments, when a TOR kinaseinhibitor is administered in combination with erlotinib, the TOR kinaseinhibitor:erlotinib ratio is less than about 1:1, less than about 1:10or less than about 1:30. In certain embodiments, when a TOR kinaseinhibitor is administered in combination with erlotinib, the TOR kinaseinhibitor:erlotinib ratio is about 1:1, about 1:10 or about 1:30.

In some embodiments, when a TOR kinase inhibitor is administered incombination with erlotinib, the TOR kinase inhibitor and erlotinib aretaken on an empty stomach, for example, at least 1 hour before and 2hours after eating.

5.5 Pharmaceutical Compositions and Routes of Administration

Provided herein are compositions comprising an effective amount of a TORkinase inhibitor and an effective amount of erlotinib or a cytidineanalog and compositions, comprising an effective amount of a TOR kinaseinhibitor and erlotinib or a cytidine analog and a pharmaceuticallyacceptable carrier or vehicle. In certain embodiments, the cytidineanalog is oral azacitidine.

In some embodiments, the pharmaceutical compositions described hereinare suitable for oral, parenteral, mucosal, transdermal or topicaladministration.

The compositions can be administered to a patient orally or parenterallyin the conventional form of preparations, such as capsules,microcapsules, tablets, granules, powder, troches, pills, suppositories,injections, suspensions and syrups. Suitable formulations can beprepared by methods commonly employed using conventional, organic orinorganic additives, such as an excipient (e.g., sucrose, starch,mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphateor calcium carbonate), a binder (e.g., cellulose, methylcellulose,hydroxymethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone,gelatin, gum arabic, polyethyleneglycol, sucrose or starch), adisintegrator (e.g., starch, carboxymethylcellulose,hydroxypropylstarch, low substituted hydroxypropylcellulose, sodiumbicarbonate, calcium phosphate or calcium citrate), a lubricant (e.g.,magnesium stearate, light anhydrous silicic acid, talc or sodium laurylsulfate), a flavoring agent (e.g., citric acid, menthol, glycine ororange powder), a preservative (e.g, sodium benzoate, sodium bisulfite,methylparaben or propylparaben), a stabilizer (e.g., citric acid, sodiumcitrate or acetic acid), a suspending agent (e.g., methylcellulose,polyvinyl pyrroliclone or aluminum stearate), a dispersing agent (e.g.,hydroxypropylmethylcellulose), a diluent (e.g., water), and base wax(e.g., cocoa butter, white petrolatum or polyethylene glycol). Theeffective amount of the TOR kinase inhibitor in the pharmaceuticalcomposition may be at a level that will exercise the desired effect; forexample, about 0.005 mg/kg of a patient's body weight to about 10 mg/kgof a patient's body weight in unit dosage for both oral and parenteraladministration.

The dose of a TOR kinase inhibitor and the dose of erlotinib or acytidine analog to be administered to a patient is rather widelyvariable and can be subject to the judgment of a health-carepractitioner. In general, the TOR kinase inhibitors, erlotinib and acytidine analog can be administered one to four times a day in a dose ofabout 0.005 mg/kg of a patient's body weight to about 10 mg/kg of apatient's body weight in a patient, but the above dosage may be properlyvaried depending on the age, body weight and medical condition of thepatient and the type of administration. In one embodiment, the dose isabout 0.01 mg/kg of a patient's body weight to about 5 mg/kg of apatient's body weight, about 0.05 mg/kg of a patient's body weight toabout 1 mg/kg of a patient's body weight, about 0.1 mg/kg of a patient'sbody weight to about 0.75 mg/kg of a patient's body weight or about 0.25mg/kg of a patient's body weight to about 0.5 mg/kg of a patient's bodyweight. In one embodiment, one dose is given per day. In any given case,the amount of the TOR kinase inhibitor administered will depend on suchfactors as the solubility of the active component, the formulation usedand the route of administration.

In another embodiment, provided herein are methods for the treatment orprevention of advanced non-small cell lung cancer comprising theadministration of about 0.375 mg/day to about 750 mg/day, about 0.75mg/day to about 375 mg/day, about 3.75 mg/day to about 75 mg/day, about7.5 mg/day to about 55 mg/day or about 18 mg/day to about 37 mg/day of aTOR kinase inhibitor in combination with erlotinib or a cytidine analogto a patient in need thereof.

In another embodiment, provided herein are methods for the treatment orprevention of advanced non-small cell lung cancer comprising theadministration of about 1 mg/day to about 1200 mg/day, about 10 mg/dayto about 1200 mg/day, about 100 mg/day to about 1200 mg/day, about 400mg/day to about 1200 mg/day, about 600 mg/day to about 1200 mg/day,about 400 mg/day to about 800 mg/day or about 600 mg/day to about 800mg/day of a TOR kinase inhibitor in combination with erlotinib or acytidine analog to a patient in need thereof. In a particularembodiment, the methods disclosed herein comprise the administration of10 mg/day, 15 mg/day, 30 mg/day, 45 mg/day, 100 mg/day, 200 mg/day, 300mg/day, 400 mg/day, 600 mg/day or 800 mg/day of a TOR kinase inhibitorin combination with erlotinib or a cytidine analog to a patient in needthereof. In one embodiment, the methods disclosed herein comprise theadministration of 10 mg/day, 15 mg/day, 30 mg/day, or 45 mg/day, of aTOR kinase inhibitor in combination with erlotinib or a cytidine analogto a patient in need thereof.

In certain embodiments, the methods provided herein comprise theadministration of between about 100 mg and about 400 mg, about 150 mgand about 350 mg or about 175 mg and about 325 mg of a cytidine analogalone or in combination with a TOR kinase inhibitor. In anotherembodiment, the methods provided herein comprise the administration ofabout 100 mg, about 200 mg or about 300 mg of a cytidine analog alone orin combination with a TOR kinase inhibitor. In a particular embodiment,the cytidine analog is oral azacitidine.

In another embodiment, the methods provided herein comprise theadministration of between about 1 mg and about 200 mg, about 10 mg andabout 175 mg or about 25 mg and about 150 mg of erlotinib alone or incombination with a TOR kinase inhibitor. In another embodiment, themethods provided herein comprise the administration of about 25 mg,about 75 mg, about 100 mg or about 150 mg of erlotinib alone or incombination with a TOR kinase inhibitor.

In another embodiment, provided herein are unit dosage formulations thatcomprise between about 1 mg and about 2000 mg, about 1 mg and about 200mg, about 35 mg and about 1400 mg, about 125 mg and about 1000 mg, about250 mg and about 1000 mg, about 500 mg and about 1000 mg, about 1 mg toabout 30 mg, about 1 mg to about 25 mg or about 2.5 mg to about 20 mg ofa TOR kinase inhibitor alone or in combination with erlotinib or acytidine analog. In another embodiment, provided herein are unit dosageformulations that comprise 1 mg, 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30mg, 35 mg, 45 mg, 50 mg, 70 mg, 100 mg, 125 mg, 140 mg, 175 mg, 200 mg,250 mg, 280 mg, 350 mg, 500 mg, 560 mg, 700 mg, 750 mg, 1000 mg or 1400mg of a TOR kinase inhibitor alone or in combination with erlotinib or acytidine analog. In another embodiment, provided herein are unit dosageformulations that comprise between about 2.5 mg, about 10 mg, about 15mg, about 20 mg, about 30 mg or about 45 mg of a TOR kinase inhibitoralone or in combination with erlotinib or a cytidine analog.

In another embodiment, provided herein are unit dosage formulations thatcomprise between about 25 mg and about 200 mg, about 50 mg and about 150mg or about 75 mg and about 150 mg of a cytidine analog alone or incombination with a TOR kinase inhibitor. In another embodiment, providedherein are unit dosage formulations that comprise about 100 mg of acytidine analog alone or in combination with a TOR kinase inhibitor.

In another embodiment, provided herein are unit dosage formulations thatcomprise between about 1 mg and about 200 mg, about 10 mg and about 175mg or about 25 mg and about 150 mg of erlotinib alone or in combinationwith a TOR kinase inhibitor. In another embodiment, provided herein areunit dosage formulations that comprise about 25 mg, about 100 mg orabout 150 mg of erlotinib alone or in combination with a TOR kinaseinhibitor.

In a particular embodiment, provided herein are unit dosage formulationscomprising about 10 mg, about 15 mg, about 30 mg, about 45 mg, about 50mg, about 75 mg, about 100 mg or about 400 mg of a TOR kinase inhibitorin combination with erlotinib or a cytidine analog.

In certain embodiments, provided herein are unit dosage formulationswherein the TOR kinase inhibitor:cytidine analog ratio is from about 1:1to about 1:10. In certain embodiments, provided herein are unit dosageformulations wherein the TOR kinase inhibitor:cytidine analog ratio isless than about 1:1, less than about 1:3 or less than about 1:10. Incertain embodiments, provided herein are unit dosage formulationswherein the TOR kinase inhibitor:cytidine analog ratio is about 1:1,about 1:3 or about 1:10.

In certain embodiments, provided herein are unit dosage formulationswherein the TOR kinase inhibitor:erlotinib ratio is from about 1:1 toabout 1:30. In certain embodiments, provided herein are unit dosageformulations wherein the TOR kinase inhibitor:erlotinib ratio is lessthan about 1:1, less than about 1:10 or less than about 1:30. In certainembodiments, provided herein are unit dosage formulations wherein theTOR kinase inhibitor:erlotinib ratio is about 1:1, about 1:10 or about1:30.

A TOR kinase inhibitor can be administered in combination with erlotinibor a cytidine analog once, twice, three, four or more times daily.

In certain embodiments, the methods provided herein compriseadministration of about 5 mg to about 100 mg, about 5 mg to about 50 mg,about 10 mg to about 50 mg or about 15 mg to about 45 mg of a TOR kinaseinhibitor in combination with about 50 mg to about 200 mg, about 75 mgto about 175 mg or about 100 mg to about 150 mg of erlotinib. In certainembodiments, the methods provided herein comprise administration ofabout 10 mg, about 15 mg, about 30 mg or about 45 mg of a TOR kinaseinhibitor in combination with about 75 mg, about 100 mg or about 150 mgof erlotinib.

In certain embodiments, the methods provided herein compriseadministration of about 5 mg to about 100 mg, about 5 mg to about 50 mg,about 10 mg to about 50 mg or about 15 mg to about 45 mg of a TOR kinaseinhibitor in combination with about 50 to about 350 mg, about 75 mg, toabout 350 mg, about 100 mg to about 350 mg, about 150 mg to about 350mg, about 175 mg to about 325 mg or about 200 mg to about 300 mg of acytidine analog. In certain embodiments, the methods provided hereincomprise administration of about 10 mg, about 15 mg, about 30 mg orabout 45 mg of a TOR kinase inhibitor in combination with about 100 mg,about 200 mg or about 300 mg of a cytidine analog, such as oralazacitidine.

In certain embodiments, the methods provided herein compriseadministration of about 10 mg, about 15 mg, about 30 mg or about 45 mgof a TOR kinase inhibitor in combination with about 75 mg, about 100 mgor about 150 mg of erlotinib.

In certain embodiments, the methods provided herein compriseadministration of about 10 mg, about 15 mg, about 30 mg or about 45 mgof a TOR kinase inhibitor in combination with about 100 mg, about 200 mgor about 300 mg of a cytidine analog.

A TOR kinase inhibitor can be administered in combination with erlotinibor a cytidine analog orally for reasons of convenience. In oneembodiment, when administered orally, a TOR kinase inhibitor incombination with erlotinib or a cytidine analog is administered with ameal and water. In another embodiment, the TOR kinase inhibitor incombination with erlotinib or a cytidine analog is dispersed in water orjuice (e.g., apple juice or orange juice) and administered orally as asuspension. In another embodiment, when administered orally, a TORkinase inhibitor in combination with erlotinib or a cytidine analog isadministered in a fasted state.

The TOR kinase inhibitor can also be administered in combination with acytidine analog intravenously, such as intravenous infusion, orsubcutaneously, such as subcutaneous injection. The mode ofadministration is left to the discretion of the health-carepractitioner, and can depend in-part upon the site of the medicalcondition.

In one embodiment, provided herein are capsules containing a TOR kinaseinhibitor in combination with erlotinib or a cytidine analog without anadditional carrier, excipient or vehicle.

In another embodiment, provided herein are compositions comprising aneffective amount of a TOR kinase inhibitor, an effective amount oferlotinib or a cytidine analog, and a pharmaceutically acceptablecarrier or vehicle, wherein a pharmaceutically acceptable carrier orvehicle can comprise an excipient, diluent, or a mixture thereof. In oneembodiment, the composition is a pharmaceutical composition.

The compositions can be in the form of tablets, chewable tablets,capsules, solutions, parenteral solutions, troches, suppositories andsuspensions and the like. Compositions can be formulated to contain adaily dose, or a convenient fraction of a daily dose, in a dosage unit,which may be a single tablet or capsule or convenient volume of aliquid. In one embodiment, the solutions are prepared from water-solublesalts, such as the hydrochloride salt. In general, all of thecompositions are prepared according to known methods in pharmaceuticalchemistry. Capsules can be prepared by mixing a TOR kinase inhibitorwith a suitable carrier or diluent and filling the proper amount of themixture in capsules. The usual carriers and diluents include, but arenot limited to, inert powdered substances such as starch of manydifferent kinds, powdered cellulose, especially crystalline andmicrocrystalline cellulose, sugars such as fructose, mannitol andsucrose, grain flours and similar edible powders.

Tablets can be prepared by direct compression, by wet granulation, or bydry granulation. Their formulations usually incorporate diluents,binders, lubricants and disintegrators as well as the compound. Typicaldiluents include, for example, various types of starch, lactose,mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such assodium chloride and powdered sugar. Powdered cellulose derivatives arealso useful. In one embodiment, the pharmaceutical composition islactose-free. Typical tablet binders are substances such as starch,gelatin and sugars such as lactose, fructose, glucose and the like.Natural and synthetic gums are also convenient, including acacia,alginates, methylcellulose, polyvinylpyrrolidine and the like.Polyethylene glycol, ethylcellulose and waxes can also serve as binders.Illustrative tablet formulations comprising Compound 1 are set forth inTables 2 and 3.

A lubricant might be necessary in a tablet formulation to prevent thetablet and punches from sticking in the die. The lubricant can be chosenfrom such slippery solids as talc, magnesium and calcium stearate,stearic acid and hydrogenated vegetable oils. Tablet disintegrators aresubstances that swell when wetted to break up the tablet and release thecompound. They include starches, clays, celluloses, algins and gums.More particularly, corn and potato starches, methylcellulose, agar,bentonite, wood cellulose, powdered natural sponge, cation-exchangeresins, alginic acid, guar gum, citrus pulp and carboxymethyl cellulose,for example, can be used as well as sodium lauryl sulfate. Tablets canbe coated with sugar as a flavor and sealant, or with film-formingprotecting agents to modify the dissolution properties of the tablet.The compositions can also be formulated as chewable tablets, forexample, by using substances such as mannitol in the formulation.

When it is desired to administer a TOR kinase inhibitor in combinationwith erlotinib or a cytidine analog as a suppository, typical bases canbe used. Cocoa butter is a traditional suppository base, which can bemodified by addition of waxes to raise its melting point slightly.Water-miscible suppository bases comprising, particularly, polyethyleneglycols of various molecular weights are in wide use.

The effect of the TOR kinase inhibitor in combination with erlotinib ora cytidine analog can be delayed or prolonged by proper formulation. Forexample, a slowly soluble pellet of the TOR kinase inhibitor incombination with erlotinib or a cytidine analog can be prepared andincorporated in a tablet or capsule, or as a slow-release implantabledevice. The technique also includes making pellets of several differentdissolution rates and filling capsules with a mixture of the pellets.Tablets or capsules can be coated with a film that resists dissolutionfor a predictable period of time. Even the parenteral preparations canbe made long-acting, by dissolving or suspending the TOR kinaseinhibitor in combination with erlotinib or a cytidine analog in oily oremulsified vehicles that allow it to disperse slowly in the serum.

In certain embodiments, the TOR kinase inhibitor is administered in aformulation set forth in U.S. Provisional Application No. 61/566,109,filed Dec. 2, 2011, which is incorporated herein in its entirety (seeparticularly page 22, paragraph [0067] to page 38, paragraph [00162] andpage 55, paragraph [00216] to page 68, paragraph [00226]).

6. EXAMPLES 6.1 Biochemical Assays

mTOR HTR-FRET Assay.

The following is an example of an assay that can be used to determinethe TOR kinase inhibitory activity of a test compound. TOR kinaseinhibitors were dissolved in DMSO and prepared as 10 mM stocks anddiluted appropriately for the experiments. Reagents were prepared asfollows:

“Simple TOR buffer” (used to dilute high glycerol TOR fraction): 10 mMTris pH 7.4, 100 mM NaCl, 0.1% Tween-20, 1 mM DTT. Invitrogen mTOR(cat#PV4753) was diluted in this buffer to an assay concentration of0.200 μg/mL.

ATP/Substrate solution: 0.075 mM ATP, 12.5 mM MnCl₂, 50 mM Hepes, pH7.4, 50 mM β-GOP, 250 nM Microcystin LR, 0.25 mM EDTA, 5 mM DTT, and 3.5μg/mL GST-p70S6.

Detection reagent solution: 50 mM HEPES, pH 7.4, 0.01% Triton X-100,0.01% BSA, 0.1 mM EDTA, 12.7 μg/mL Cy5-αGST Amersham (Cat#PA92002V), 9ng/mL α-phospho p70S6 (Thr389) (Cell Signaling Mouse Monoclonal #9206L),627 ng/mL α-mouse Lance Eu (Perkin Elmer Cat#AD0077).

To 20 μL of the Simple mTor buffer is added 0.5 μL of test compound inDMSO. To initiate the reaction 5 μL of ATP/Substrate solution was addedto 20 μL of the Simple TOR buffer solution (control) and to the compoundsolution prepared above. The assay was stopped after 60 min by adding 5μL of a 60 mM EDTA solution; 10 μL of detection reagent solution wasthen added and the mixture was allowed to sit for at least 2 hoursbefore reading on a Perkin-Elmer Envision Microplate Reader set todetect LANCE Eu TR-FRET (excitation at 320 nm and emission at 495/520nm).

TOR kinase inhibitors were tested in the mTor HTR-FRET assay and werefound to have activity therein, with certain compounds having an IC₅₀below 10 μM in the assay, with some compounds having an IC₅₀ between and0.005 nM and 250 nM, others having an IC₅₀ between and 250 nM and 500nM, others having an IC₅₀ between 500 nM and 1 μM, and others having anIC₅₀ between 1 μM and 10 μM.

6.2 Cell Based Assays

Cell Viability Assay for Cell Lines.

Compound 1 and second agent (azacitidine or erlotinib) were added to a384-well flat, clear bottom, black polystyrene, TC-Treated plate(Cat#3712, Corning, MA) via an acoustic dispenser (EDC Biosystems). BothCompound 1 and the second agent were serially diluted 3-fold across theplate for ten concentrations in triplicate at 3 different compoundratios. Both compounds were also added alone to determine their affectsas single agents. DMSO (no compound) was used as control for 100%viability and background (no cells). Final assay DMSO concentration was0.2% (v/v). Three different combinatory sequence of additions weretested. In the first instance, both Compound 1 and the second agent wereadded simultaneously (Sim) into an empty plate. Cells were then addeddirectly on top of the compounds at an optimized density to ensure thatthe cell growth was within the linear detection range of the assay afterthree days in culture. In the second instance, Compound 1 was added intoan empty plate followed immediately with the addition of cells. After 24hours in culture, the second agent was then added to the previous plateand allowed to incubate for an additional 48 hours (SeqM1). Thus thetreatment time for Compound 1 and the second agent were 72 and 48 hours,respectively. In the third instance, the second agent was added into anempty plate followed immediately with the addition of cells. After 24hours in culture, Compound 1 was then added to the previous plate andallowed to incubate for an additional 48 hours (SeqM2). Thus thetreatment time for Compound 1 and the second agent were 48 and 72 hours,respectively. After 72 hours of total incubation, cell viability wasdetermined using Promega's CellTiter-Glo Luminescent Cell ViabilityAssay (Cat#G7573, Promega, WI) using the manufacturer's standardoperating procedures. Background subtracted luminescence counts wereconverted to percentages of cell viability with respect to DMSO treatedcontrol cells.

Dose response curves were generated using XLFit4 (IDBS, UK) by fittingthe percentage of control data at each concentration using a 4 ParameterLogistic Model/Sigmoidal Dose-Response Model[y=(A+4B−A)/(1+((C/x)^D))))]. To evaluate the combinatory effect of thetwo agents on a cell line, data was analyzed by comparing itscombinatory response against the theoretical additive response of thetwo agents alone. The expected additive effect of two agents (A and B)can be calculated using the fractional product method (Webb 1961, Enzymeand Metabolic Inhibitors, New York: Academic Press): (fu)A,B=(fu)A×(fu)Bwhere fu=fraction unaffected by treatment. Synergism of a combination isdetermined when the observed fraction unaffected in combination is lessthan (fu)A,B, while an additive effect is determined when the observedfraction unaffected in combination=(fu)A,B.

Alternatively, the calculation of combination index (CI) based off ofChou-Talalay mathematical modeling was used to evaluate the combinatoryeffect of the two agents. IC₅₀ values, which are the effective dose atwhich a 50% inhibition is achieved, were calculated for each singleagent as well as the combined agents and used to calculated theirrespective CI values. The CI value indicates synergism as shown in Table1 below (Chou and Talalay, 1983, Trends Pharmacol. Sci. (4) 450-454).

TABLE 1 Index (CI) Description   <0.1 Very strong synergism 0.1-0.3Strong synergism 0.3-0.7 Synergism  0.7-0.85 Moderate synergism0.85-0.90 Slight synergism 0.90-1.10 Nearly additive 1.10-1.20 Slightantagonism 1.20-1.45 Moderate antagonism 1.45-3.3  Antagonism 3.3-10 Strong antagonism >10 Very strong antagonism

Results (CI values) are set forth in Table 2-4 and FIGS. 1-4. Synergy isobserved for many of the combinations of Compound 1+azacitidine andCompound 1+erlotinib.

TABLE 2 Simultaneous compound addition NSCLC Cell Comp. 1: azacitidineratio Comp. 1: erlotinib ratio Line 1:1 1:3 1:10 1:1 1:10 1:30 A549 0.950.87 0.80 0.82 0.63 0.56 H1755 0.90 0.73 0.72 1.13 0.79 0.60 H460 1.170.85 0.82 1.47 0.89 0.60 H838 1.09 0.90 0.93 0.73 0.92 0.59 H1792 0.780.70 0.71 1.75 1.00 0.69 H1975 1.25 1.09 0.95 1.16 0.94 0.62 H226 0.960.84 0.91 1.20 0.74 0.49 Hop92 1.05 0.61 0.63 1.87 1.18 0.82 Median CI1.01 0.85 0.81 1.18 0.91 0.60

TABLE 3 Compound 1 first followed by second agent (SeqM1) NSCLC CellComp. 1: azacitidine ratio Comp. 1: erlotinib ratio Line 1:1 1:3 1:101:1 1:10 1:30 A549 1.05 0.92 0.78 0.90 0.72 0.65 H1755 0.82 0.67 0.610.81 0.64 0.47 H460 0.80 0.80 0.90 1.08 0.81 0.60 H838 1.09 0.99 0.881.01 0.90 0.65 H1792 0.63 0.56 0.60 1.04 0.90 0.60 H1975 1.00 0.98 0.991.05 0.75 0.54 H226 1.06 1.02 0.98 0.82 0.91 0.74 Hop92 0.86 0.73 0.801.23 0.71 0.49 Median CI 0.93 0.86 0.84 1.03 0.78 0.60

TABLE 4 Second agent first followed by Compound 1 (SeqM2) NSCLC CellComp. 1: azacitidine ratio Comp. 1: erlotinib ratio Line 1:1 1:3 1:101:1 1:10 1:30 A549 0.85 0.70 0.69 1.01 0.73 0.60 H1755 0.60 0.60 0.650.89 0.78 0.74 H460 0.73 0.74 0.79 2.14 0.81 0.59 H838 0.66 0.68 0.851.04 0.83 0.75 H1792 0.73 0.68 0.66 0.79 0.64 0.43 H1975 0.63 0.65 0.661.32 0.69 0.60 H226 0.41 0.46 0.54 0.46 0.74 0.64 Hop92 0.51 0.47 0.522.73 0.82 0.57 Median CI 0.64 0.66 0.66 1.02 0.76 0.60

As can be seen in the tables and figures, both 5-azacitidine anderlotinib showed synergy with Compound 1 in multiple NSCLC lines invitro. The sequence of addition affected the combinatorial effect forCompound 1 and the 5-azacitidine combination. The best combinatorialeffect was observed when 5-azacitidine was added prior to treatment withCompound 1. For the Compound 1 and erlotinib combination, the ratio oftwo agents instead of sequence of addition affected the CI values. Thebest molar ratio was 1:30 for Compound 1:erlotinib.

6.3 In Vivo Assays

DM179—Non Small Cell Lung Cancer Primary TumorGraft.

DM179 is a primary tumorgraft model derived from tumor tissues obtainedfrom a NSCLC patient. Compound 1 and the second agents are tested assingle agents and Compound 1 is tested in combination with the secondagent (erlotinib or azacitidine) in the model. Nude mice are inoculatedsubcutaneously with DM179 low passage tumor fragments in the flankregion. Following inoculation of the animals, the tumors are allowed togrow to about 200 mm³ prior to randomization. Animals bearing DM179tumors of about 200 mm³ are pooled together and randomized into varioustreatment groups. Compound 1 is formulated in 0.5% CMC and 0.25% Tween80 in water (as a suspension). The animals are orally administeredvehicle (CMC-Tween) or Compound 1 alone or in combination with thesecond agent, for example, once daily (QD) for up to 21 days. Treatmentwith Compound 1 and the second agents is either simultaneous orstaggered. Doses of Compound 1 can range between 1 and 10 mg/kg anddoses for the second agent or the combination are determined based onsingle agent experiment results or literature reports. The positivecontrol paclitaxel (20 mg/kg, Q7Dx4) is administered via intravenous(IV) route. Tumors are measured twice a week using calipers and tumorvolumes are calculated using the formula of W²×L/2 (W=width, L=length).

BML-5—Non Small Cell Lung Cancer Primary TumorGraft.

BML-5 is a primary tumorgraft model derived from tumor tissues obtainedfrom NSCLC patient. Compound 1 and the second agents are tested assingle agents and Compound 1 is tested in combination with the secondagent (erlotinib or azacitidine) in the model. Nude mice are inoculatedsubcutaneously with BML-5 low passage tumor fragments in the flankregion. Following inoculation of the animals, the tumors are allowed togrow to about 200 mm³ prior to randomization. Animals bearing BML-5tumors of about 200 mm³ are pooled together and randomized into varioustreatment groups. Compound 14 is formulated in 0.5% CMC and 0.25% Tween80 in water (as a suspension). The animals are orally administeredvehicle (CMC-Tween), Compound 1 alone or in combination with the secondagent, for example, once daily (QD) for up to 21 days. Treatment withCompound 1 and the second agents is either simultaneous or staggered.Doses of Compound 1 can range between 1 and 10 mg/kg and doses for thesecond agent or the combination are determined based on single agentexperiment results or literature reports. The positive control Docetaxel(20 mg/kg, Q7Dx3) is administered via intravenous (IV) route. Tumors aremeasured twice a week using calipers and tumor volumes are calculatedusing the formula of W²×L/2.

ST140—Non Small Cell Lung Cancer Primary TumorGraft.

ST140 is a primary tumorgraft model derived from tumor tissues obtainedfrom NSCLC patient. Compound 1 and the second agents are tested assingle agents and Compound 1 is tested in combination with the secondagent (erlotinib or azacitidine) in the model. Nude mice are inoculatedsubcutaneously with ST-140 low passage tumor fragments in the flankregion. Following inoculation of animals, the tumors are allowed to growto about 200 mm³ prior to randomization. Animals bearing ST140 tumors ofabout 200 mm³ are pooled together and randomized into various treatmentgroups. Compound 1 is formulated in 0.5% CMC and 0.25% Tween 80 in water(as a suspension). The animals are orally administered vehicle(CMC-Tween), Compound 1 alone or in combination with the second agent,for example, once daily (QD) for up to 21 days. Treatment with Compound1 and the second agents is either simultaneous or staggered. Doses ofCompound 1 can range between 1 and 10 mg/kg and doses for the secondagent or the combination are determined based on single agent experimentresults or literature reports. The positive control Docetaxel (20 mg/kg,Q7Dx3) is administered via intravenous (IV) route. Tumors are measuredtwice a week using calipers and tumor volumes are calculated using theformula of W²×L/2

Selected TOR kinase inhibitors show, or are expected to show, synergy inthe models when used in combination with erlotinib or azacitidine.

6.4 Alternative Combination Studies with Compound 1

Proliferation Assays.

NSCLC cell lines and their sensitivities expressed as IC₅₀ values forerlotinib and the TOR kinase inhibitor Compound 1 are shown in Table 5.

TABLE 5 Cell Line Histology KRAS EGFR Erlotinib IC50 Compound 1 IC50A549 ACA MUT G125 WT R > 10 μM (25.2) IC50 0.58 μM Calu-3 ACA WT wt(HER2+) I, 7.09 μM IC50 0.184 μM H1299 Large Cell Neuroendocrin WT WT I,IC50 > 10 μM IC50 3.09 μM H157 SQC MUT-[c.34G.C; WT R, IC50 > 10 mM IC502.61 μM H1650 ACA WT E746 A750del (exon19) I, IC50 2.84 μM IC50 5.20 μMH1703 SCC WT WT R > 10 μM IC50 1.64 μM H1975 ACA WT L858R, T790M I (R >10 μM IC50 0.25 μM H2009 ACA MUT WT R, IC50 μM (15.3) IC50 5.05 μM H2122ACA MUT WT R, IC50 > 10 μM IC50 1.59 μM H2126 ACA WT WT R, IC > 10 μM(19.8) IC50 0.214 μM H226 SQC WT WT R, IC50 > 10 μM IC50 1.98 μM H322cACA WT WT R H3255 ACA ND L858R S, 0.205 μM IC50 11.87 μM H441 ACA, BACMUT WT R, IC50 > 10 μM IC50 0.392 μM H460 LCC MUT G61H WT R, IC50 > 10μM (18.0) IC50 0.153 μM H520 SQC WT WT R, IC50 > 10 μM IC50 0.374 μMH720 carcinoid H727 carcinoid MUT WT H820 ACA WT (L747_L75 I del, T790M(exon 1) I HCC15 SQC WT WT R, IC50 > 10 μM IC50 6.37 μM HCC193 ACA WT WTHCC4006 ACA WT L747 E749del, A750P S HCC95 SQC WT WT I (6.45 μM) IC500.724 μM NCI-H23 ACA MUT 12 mutation G12C R, IC50 > 10 μM (22.8) IC503.00 μM

Compound 1 and erlotinib demonstrated anti-proliferative activity in apanel of NSCLC cell lines with various degrees of sensitivity asreflected in different IC₅₀ values.

Combination Indices.

This study was performed using erlotinib resistant cell lines A549,H1975, H1650, and HCC95. These cell lines display different degrees oferlotinib resistance and possess different genetic backgrounds withregard to mutation status in EGFR and KRAS. In combination witherlotinib, Compound 1 showed synergistic anti-proliferative effects inNSCLC cell lines resistant to erlotinib. The results are shown in FIGS.5A-5D. The synergy was more pronounced at lower concentrationsdisplaying combination indices down to 0.1-0.2, indicating strongsynergy (for CI value interpretation, see Table 1). These resultsindicate that Compound 1 is capable of overcoming drug resistance toerlotinib in NSCLC cells showing synergistic effects with combinationtreatment.

Table 6 shows the levels of synergy for the combination of erlotinib andCompound 1, in a NSCLC wild-type cell line (A549), a cell line (H3255)with an EGFR activating mutant (L858R), and in a cell line (H1975) witha mutation of EGFR (T790M), which is erlotinib resistant. As can beseen, synergy, as defined by Table 1, was observed in all cell types,including the erlotinib resistant cell line H1975 (ND=not determined).

TABLE 6 Erlotinib Compound 1 CI in CI in H3255 CI in H1975 concentrationconcentration A549 (EGFR act. (EGFRi (μM) (μM) (WT) mutant) resistant)0.1 0.01 ND 41.958 ND 0.1 0.1 14.01 0.1 0.3 0.195 0.1 0.6 0.224 0.1 10.34 0.1 3 0.89 0.1 6 1.308 0.1 10 2.921 0.1 15 3.621 0.5 0.01 0.6561.23 1.497 0.5 0.1 0.402 0.06 0.518 0.5 0.3 0.419 0.125 0.262 0.5 0.60.347 0.136 0.223 0.5 1 0.342 0.265 0.22 0.5 3 0.592 0.635 0.628 0.5 61.132 1.926 1.722 0.5 10 1.782 2.258 1.9 0.5 15 2.253 3.242 1.86 1 0.010.439 0.239 0.614 1 0.1 0.243 0.175 1.385 1 0.3 0.255 0.201 0.298 1 0.60.179 0.163 0.307 1 1 0.245 0.266 0.373 1 3 0.274 0.721 1.06 1 6 0.5311.694 1.587 1 10 0.963 3.261 1.297 1 15 1.251 3.996 1.32 5 0.01 0.664 ND0.97 5 0.1 0.355 0.712 5 0.3 0.364 0.452 5 0.6 0.302 0.358 5 1 0.2420.585 5 3 0.289 1.165 5 6 0.598 3.139 5 10 0.992 1.456 5 15 1.344 1.512

Cell Cycle Analysis.

In cell cycle analysis, the use of propidium iodide staining showedincreased cell cycle arrest for the combination treatment using Compound1 and erlotinib with a decrease of the S-phase and an increase of theG0/G1 phase. The results of these studies are shown in FIG. 6. Theseresults indicate that Compound 1 in combination with erlotinib causedcell cycle arrest in NSCLC cells.

Biomarker Analysis Using Western Blotting.

Data for pathway inhibition analyses are shown in FIGS. 7A and 7B inseveral cell types. The data indicate that the combination of Compound 1and erlotinib demonstrated inhibition of a signaling component in themTOR pathway, namely p4EBP1.

In Vivo Studies of Compound 1 alone or in Combination with Erlotinib inA549 and H1975 Xenografts in Nude Mice.

A549 adenocarcinoma or H1975 cells in single cell suspension wereimplanted into the posterior flanks of athymic nude mice. The controlgroup was treated with vehicle, the other groups were treated witherlotinib at 40 mg/kg 3× per week oral gavage, Compound 1 at 5mg/kg/daily oral gavage, or a combination of erlotinib at 40 mg/kg andCompound 1 at 5 mg/kg. For the A549 xenograft, the treatments werestarted on Day 26 after implantation and were stopped on day 53, whilefor the H1975 xenograft, the treatments were started on day 17 afterimplantation and were stopped on day 30.

As can be seen in FIG. 8, when compared to the untreated control group,the A549 xenograft was resistant to the treatment with erlotinib at 40mg/kg 3× per week. When Compound 1 was combined with erlotinib at 40mg/kg 3× per week, tumor growth was effectively suppressed. The tumorgrowth increased when the treatment with combination of Compound 1 anderlotinib was stopped, but at a considerably slower rate compared to thesingle treatment groups.

As can be seen in FIG. 9, when compared to the control group, the H1975xenograft was moderately sensitive to the treatment with erlotinib at 40mg/kg 3× per week. When Compound 1 was combined with erlotinib at 40mg/kg 3× per week, tumor growth was inhibited.

Conclusions.

Compound 1 demonstrated anti-proliferative activity in a panel of NSCLCcell lines. In NSCLC cells resistant to the EGFR tyrosine kinaseinhibitor erlotinib, Compound 1 combined with erlotinib demonstratedsynergistic anti-proliferative effects. Synergistic effects of Compound1 and erlotinib were also demonstrated in suppression of tumor growth inA549 xenografts. Synergistic effects of Compound 1 and erlotinib werealso demonstrated in the growth inhibition of H1975 xenografts. Themechanism for the synergistic effects were found to involve changes incell cycle arrest. Analyses of signaling pathway inhibition using thedrug combinations showed inhibition of signaling components in the mTORpathway.

6.5 Clinical Study

A Phase 1b, Multi-Center, Open-Label Study of the mTOR Kinase InhibitorCompound 1 in Combination with Erlotinib or Oral Azacitidine in AdvancedNon-Small Cell Lung Cancer.

This will be a Phase 1b, multi-center, open-label study of the TORKinase Inhibitor Compound 1 in combination with erlotinib or oralazacitidine in advanced non-small cell lung cancer.

The primary objectives of the study are to determine the safety andtolerability of Compound 1 when administered orally in combination witheither erlotinib or oral azacitidine and to define the non-tolerateddose (NTD) and the maximum tolerated dose (MTD) of each combinationusing NCl CTCAE v4; and to characterize the pharmacokinetics (PK) ofCompound 1 and azacitidine following oral administration as singleagents and after combination treatment. The secondary objectives of thestudy are to evaluate the effect of study drugs on mTORC1 and mTORC2pathway biomarkers in blood and tumor; provide information on thepreliminary efficacy of each drug combination; and characterize the PKof Compound 1 M1 metabolite after oral administration of Compound 1 as asingle agent and in combination with erlotinib or oral azacitidine.

This is a clinical study of Compound 1 administered orally incombination with either oral erlotinib or oral azacitidine in subjectswith Stage IIIB/IV NSCLC who have failed at least one line of standardtherapy. It is a Phase 1b dose escalation and expansion study evaluatingescalating dose levels of Compound 1 in combination with two dose levelsof erlotinib (Arm A) or two dose levels of oral azacitidine administeredeither concurrently with Compound 1 (Arm B), or sequentially withCompound 1 (Arm C), followed by expansion of each combination cohort atone or more selected doses.

In Arm A, cohorts will receive escalating continuous daily doses (15 mg,30 mg, and 45 mg) of Compound 1 in capsules concurrently with at leasttwo different daily dose levels of erlotinib tablets (100 mg and 150 mg)in 28 day cycles after an initial single dose of Compound 1 seven daysbefore, and a single dose of erlotinib on the first day of, the firstcycle.

In Arm B, cohorts will receive escalating continuous daily dose levelsof Compound 1 (15 mg, 30 mg, and 45 mg) concurrently with one or moredose levels of oral azacitidine (200 mg or 300 mg, as two or three 100mg tablets) administered on Day 1 to 21 of each 28-day cycle after aninitial single dose of Compound 1 seven days before, and a single doseof oral azacitidine on the first day of, the first cycle.

In Arm C, cohorts will receive escalating daily dose levels of Compound1 (15 mg, 30 mg, and 45 mg) administered on Day 8 to 28 after one ormore dose levels of oral azacitidine (200 mg or 300 mg, as two or three100 mg tablets) administered on Day 1 to 7 of each 28-day cycle after aninitial single dose of Compound 1 seven days before the first cycle.

A standard “3+3” dose escalation design will be used to identify initialtoxicity of each combination. Subjects will be assigned to studytreatment arms based on Investigator choice and open slots. Cohorts of 3subjects will take study drugs in defined dose increments and, in theevent of dose-limiting toxicity (DLT) in 1 of 3 evaluable subjects,cohorts will be expanded to 6 subjects.

An evaluable subject for DLT is defined as one that received at least 20of the 27 planned doses of Compound 1, and 21 of the 28 planned doses oferlotinib, during Cycle 1 in Arm A; received at least 20 of the 27planned doses of Compound 1, and 14 of 21 planned doses of oralazacitidine, during Cycle 1 in Arm B; received at least 14 of 21 planneddoses of Compound 1, and 6 of 7 planned doses of oral azacitidine,during Cycle 1 in Arm C; experienced study drug-related DLT afterreceiving at least one dose.

Non-evaluable subjects not due to DLT will be replaced. Additionalsubjects within any dose cohort may be enrolled at the discretion of theSafety Review Committee (SRC).

A dose will be considered the NTD when 2 of 6 evaluable subjects in acohort experience drug-related DLT in Cycle 1. The MTD is defined as thelast dose level below the NTD with 0 or 1 out of 6 evaluable subjectsexperiencing DLT during Cycle 1. If 2 of 6 DLT are observed at the firstdose level with either combination, a lower dose combination may beexplored at the discretion of the SRC. An intermediate dose of Compound1 (one between the NTD and the last dose level before the NTD) may beevaluated to accurately determine the MTD of the combination.

Following completion of dose escalation, each combination treatment armwill be expanded with approximately 10 additional evaluable subjects.Expansion may occur at the MTD established in the dose escalation phase,or at an alternative tolerable combination dose level, based on thereview of safety, PK and PD data.

Tumor biopsy for analysis of genetic mutations and biomarkers oftreatment activity is optional in the dose escalation phase butmandatory during the dose expansion phase. Paired tumor biopsies toevaluate tumor biomarkers of Compound 1, erlotinib and/or oralazacitidine activity will be required in the expansion cohorts.

The study population will consist of men and women, 18 years or older,with Stage IIIB/IV NSCLC, with disease progression following at leastone standard first-line treatment regimen. First-line treatment mayinclude either chemotherapy or an EGFR inhibitor.

Enrollment is expected to take approximately 15 months (9 months fordose escalation, 6 months for expansion). Completion of active treatmentand post treatment follow-up is expected to take 6-12 additional months.

Dose levels to be explored in this Phase 1b study are shown below.

Arm A Arm B and C Cmpd 1 Cmdp 1 (mg) Oral Azacitidine (mg) Dose (mgErlotinib Arm B: D-7, D2-28 Arm B: D1-21 Level daily) (mg daily) Arm C:D-7, D8-28 Arm C: D1-D7 1 15 100 15 200 2a 15 150 15 300 2b 30 100 30200 3a 30 150 30 300 3b 45 100 45 200 4 45 150 45 300

If unacceptable toxicity occurs at dose level 1, only one dose reductionfor each drug is allowed: Compound 110 mg, erlotinib 75 mg, and oralazacitidine 100 mg.

Dose levels 2a and 2b and dose levels 3a and 3b have comparable doseintensity and may be enrolled concurrently.

Treatment is administered in 28-day cycles. Compound 1 and erlotinibwill be dosed daily in Arm A; oral azacitidine will be dosed concurrentwith daily Compound 1 for the first 21 of 28 days in Arm B; oralazacitidine will be dosed only for 7 days before dosing with Compound 1alone for 21 of 28 days in Arm C. For both the dose escalation andexpansion phases, slight modifications to the dosing schedule will occurprior to and during Cycle 1 in order to facilitate PK and PD evaluationof each drug alone and in combination. Administration of study drugs isdescribed below:

In Arm A, B and C:

-   -   One week (Day −7) prior to Cycle 1, a single dose of Compound 1        will be administered followed by PK and PD sampling.

In Arm A:

-   -   During Cycle 1, a single oral dose of erlotinib will be        administered on Day 1. Combined administration with Compound 1        will start on Day 2 and continue through Day 28.    -   Starting with Cycle 2 and thereafter, both drugs will start on        Day 1 and continue through Day 28.

In Arm B:

-   -   During Cycle 1, a single dose of oral azacitidine will be        administered on Day 1. Combined administration with Compound 1        will start on Day 2. Oral azacitidine will continue through Day        21 and Compound 1 through Day 28.    -   Starting with Cycle 2 and thereafter, both drugs will start on        Day 1. Oral azacitidine will continue through Day 21 and        Compound 1 through Day 28.

In Arm C:

-   -   During all cycles, oral azacitidine will be administered on Day        1 through 7 and Compound 1 will be administered on Day 8 through        28.

After the first dose is administered on Day 1 in any cohort, subjectswill be observed for at least 28 days before the next higherprotocol-specified dose cohort can begin. Intra-subject dose escalationof study drugs is not permitted during Cycle 1 but may be permitted incycles beyond Cycle 1 if approved by the SRC. Dose reduction andtemporary interruption of one or both drugs due to toxicity is allowed,but dose reduction during Cycle 1 will constitute DLT.

Study drugs are taken together at approximately the same time eachmorning. Due to a significant interaction of erlotinib with food,subjects in Arm A must take study drugs on an empty stomach at least 1hour before and 2 hours after eating. There are no such foodrestrictions for subjects taking Compound 1 or oral azacitidine in ArmsB and C.

Study treatment may be discontinued if there is evidence of diseaseprogression, unacceptable toxicity or subject/physician decision towithdraw. Subjects may continue to receive study drugs beyond diseaseprogression at the discretion of the Investigator.

The estimated total number of subjects to be enrolled during doseescalation is 54 to 108, depending on cohort size. Approximately 30additional subjects (10 per regimen) will be evaluated for safety, PK,PD and preliminary antitumor effects during the expansion phase.

Subjects will be evaluated for efficacy after every 2 cycles throughCycle 6 and every 3 cycles thereafter. All treated subjects will beincluded in the efficacy analysis. The primary efficacy variable istumor response rate and by progression-free survival at the end of 4cycles of treatment. Tumor response will be determined by theInvestigator, based on Response Evaluation Criteria in Solid Tumors(RECIST 1.1; Eisenhauer E. A., Therasse P., Bogaerts J., et al. Newresponse evaluation criteria in solid tumours: Revised RECIST guideline(version 1.1). European J. Cancer; 2009; (45) 228-247)).

Secondary and exploratory endpoints include evaluation of mTOR, EGFR,and oral azacitidine biomarkers in blood and/or tumor and exploration ofPK, PD, toxicity, and activity relationships.

The safety variables for this study are adverse events (AEs), safetyclinical laboratory variables, 12-lead electrocardiograms (ECGs), leftventricular ejection fraction (LVEF) assessments, physical examinations,vital signs, exposure to study treatment, assessment of concomitantmedications, and pregnancy testing for females of child bearingpotentials (FCBP).

During dose escalation, the decision to either evaluate a higher doselevel or declare an MTD will be determined by the SRC, based on theirreview of all available clinical and laboratory safety data for a givendose cohort.

The SRC will also select the dose and schedule of Compound 1 incombination with erlotinib and oral azacitidine appropriate for cohortexpansion. One or both schedules of Compound 1 and oral azacitidine maybe selected for cohort expansion. The SRC will continue to review safetydata regularly throughout the study and make recommendations about studycontinuation and dose modification, as appropriate.

The concentration-time profiles of Compound 1, M1, erlotinib and oralazacitidine will be determined from serial blood samples collected afteradministration of study drugs as single agents and after combinationtreatment. The pharmacokinetics (PK) of Compound 1 and azacitidine willbe determined after oral administration of each drug as a single agentand after combination treatment (Compound 1/oral azacitidine) using: (1)Maximum observed concentration in plasma (C_(max)), (2) Area under theconcentration-time curve (AUC), (3) Time to maximum concentration(t_(max)), (4) Terminal half-life (T_(1/2)), (5) Apparent total bodyclearance (CL/F) and (6) Apparent volume of distribution (Vz/F).

The effect of erlotinib and oral azacitidine on Compound 1 and M1 PKwill be assessed, as will the effect of Compound 1 on the PK oferlotinib and oral azacitidine. Systemic exposure of Compound 1 afteradministration of Compound 1 as a single agent and in combination witherlotinib or oral azacitidine will be correlated with safety, PD andactivity outcomes. The principal metabolites of Compound I, includingM1, will be quantified in plasma. The PK of the M1 metabolite after oraladministration of Compound I as a single agent and in combination witherlotinib or oral azacitidine will be characterized.

Biomarker evaluation will include analysis of mTOR pathway biomarkers,and other signaling pathways when possible, in blood and tumor afterboth single agent and combination treatment. In some instances, thechanges of each biomarker will be determined by comparing the levels ofbiomarkers in pre- and on-treatment samples and, where possible,correlate these with PK findings and tumor response over time.

Assessment of gene DNA methylation and expression status in blood andtumor (when available) will be assessed at baseline and duringcombination drug treatment in Arm B and C to explore potentialpredictors of sensitivity to the Compound 1 plus oral azacitidinecombination and effect of combination treatment on DNA methylation andexpression.

Tumor gene sequencing will be performed at baseline on archival orScreening tumor biopsies to test for multiple genomic abnormalities.

Inclusion criteria for the study are: (1) Men and women, 18 years orolder, with histologically or cytologically-confirmed, Stage IIIB/IVNon-Small Cell Lung Cancer with tumor progression following at least oneprior treatment regimen (either chemotherapy or an Epidermal GrowthFactor Receptor inhibitor for advanced disease), (2) Eastern CooperativeOncology Group Performance Score of 0 or 1, (3) the following laboratoryvalues: Absolute Neutrophil Count (ANC)≧1.0×10⁹/L; hemoglobin (Hgb)≧9g/dL; platelets (plt)≧100×10⁹/L; potassium within normal limits orcorrectable with supplements; AST/SGOT and ALT/SGPT ≦2.5× Upper Limit ofNormal (ULN) or ≦5.0×ULN if liver tumor is present; serum bilirubin≦1.5×ULN; estimated serum creatinine clearance of ≧60 mL/min/1.73 m²using the Cockcroft-Gault equation; subjects who complete Cycle 1 mustmeet the following hematologic criteria at the beginning of eachsubsequent cycle: ANC>1.0×10⁹/L; and platelets>75×10⁹/L; and if thehematologic criteria are not met, the start of oral azacitidine insubsequent cycles may be delayed for up to 7 days to allow recovery. Ifrecovery has not occurred after 7 days, this will be considered a DLT,(4) Adequate contraception (if appropriate), (5) Consent to retrievearchival tumor tissue, and (6) Consent to repeated tumor biopsy (doseexpansion phase).

Exclusion criteria for the study are: (1) Prior systemic cancer-directedtreatments or investigational drugs within 4 wks or 5 half lives,whichever is shorter, (2) Symptomatic central nervous system metastases,(3) Known acute or chronic pancreatitis, (4) Subjects with persistentdiarrhea or malabsorption ≧NCI CTCAE grade 2, despite medicalmanagement, (5) Impaired cardiac function or significant cardiacdisease, any of the following: LVEF <45% as determined by MUGA or ECHO;complete left bundle branch or bifascicular block; congenital long QTsyndrome; persistent or clinically meaningful ventricular arrhythmias;QTcF>460 msec on Screening ECG (mean of triplicate recordings); unstableangina pectoris or myocardial infarction ≦3 months prior to startingstudy drugs; uncontrolled hypertension (blood pressure ≧160/95 mmHg);(6) Diabetes on active treatment with either of the following: Fastingblood glucose (FBG)>126 mg/dL (7.0 mmol/L) or HbA1c≧6.5%, (7) KnownHuman Immunodeficiency Virus infection, chronic active hepatitis B or Cvirus infection, (8) Prior treatment with an investigational dualTORC1/TORC2, PI3K, or AKT inhibitor, (9) Major surgery ≦2 weeks prior tostarting study drugs; no specific wash out is required for radiotherapy.Subjects must have recovered from any effects of recent therapy thatmight confound the safety evaluation of study drug, (10) Women who arepregnant or breast feeding. Adults of reproductive potential notemploying two forms of birth control, and (11) history of concurrentsecond cancers requiring ongoing systemic treatment.

In some embodiments, patients undergoing the clinical protocol providedherein will show a positive tumor response, such as inhibition of tumorgrowth or a reduction in tumor size. In certain embodiments, patientsundergoing the clinical protocol provided herein will achieve a ResponseEvaluation Criteria in Solid Tumors (for example, RECIST 1.1) ofcomplete response, partial response or stable disease afteradministration of an effective amount of compound 1 in combination withan effective amount of erlotinib or oral azacytidine. In certainembodiments, patients undergoing the clinical protocol provided hereinwill show increased survival without tumor progression. In someembodiments, patients undergoing the clinical protocol provided hereinwill show inhibition of disease progression, inhibition of tumor growth,reduction of primary tumor, relief of tumor-related symptoms, inhibitionof tumor secreted factors (including tumor secreted hormones, such asthose that contribute to carcinoid syndrome), delayed appearance ofprimary or secondary tumors, slowed development of primary or secondarytumors, decreased occurrence of primary or secondary tumors, slowed ordecreased severity of secondary effects of disease, arrested tumorgrowth and regression of tumors, increased Time To Progression (TTP),increased Progression Free Survival (PFS), and/or increased OverallSurvival (OS), among others.

6.6 Compound 1 Formulations

Illustrative formulations of Compound 1 useful in the methods providedherein are set forth in Tables 7 and 8, below.

TABLE 7 Amounts Ingredients mg % Compound 1 20.0 15.38 Lactosemonohydrate, NF (Fast Flo 316) 63.98 49.22 Microcrystalline cellulose,NF (Avicel pH 102) 40.30 31.00 Croscarmellose sodium, NF (Ac-Di-Sol)3.90 3.00 Stearic acid, NF 0.52 0.40 Magnesium Stearate, NF 1.30 1.00Total 130.0 100 Opadry yellow 03K12429 4% weight gain

TABLE 8 Amounts Ingredients mg % Compound 1 5.0 3.80 Lactosemonohydrate, NF (Fast Flo 316) 78.98 60.70 Microcrystalline cellulose,NF (Avicel pH 102) 40.30 31.00 Croscarmellose sodium, NF (Ac-Di-Sol)3.90 3.00 Stearic acid, NF 0.52 0.40 Magnesium Stearate, NF 1.30 1.00Total 130.0 100 Opadry II pink 85F94211 5.2 4% weight gain

A number of references have been cited, the disclosures of which areincorporated herein by reference in their entirety. The embodimentsdisclosed herein are not to be limited in scope by the specificembodiments disclosed in the examples which are intended asillustrations of a few aspects of the disclosed embodiments and anyembodiments that are functionally equivalent are encompassed by thepresent disclosure. Indeed, various modifications of the embodimentsdisclosed herein are in addition to those shown and described hereinwill become apparent to those skilled in the art and are intended tofall within the scope of the appended claims.

What is claimed is:
 1. A method for treating advanced non-small celllung cancer, comprising administering an effective amount of7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((1r,4r)-4-methoxycyclohexyl)-3,4-dihydropyrazino-[2,3-b]pyrazin-2(1H)-oneor a pharmaceutically acceptable salt, stereoisomer or tautomer thereofin combination with an effective amount of erlotinib or azacitidine to apatient having advanced non-small cell lung cancer, wherein the ratio of7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((1r,4r)-4-methoxycyclohexyl)-3,4-dihydropyrazino-[2,3-b]pyrazin-2(1H)-oneor a pharmaceutically acceptable salt, stereoisomer or tautomer thereofto erlotinib is about 1:10 to about 1:100 and the ratio of7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((1r,4r)-4-methoxycyclohexyl)-3,4-dihydropyrazino-[2,3-b]pyrazin-2(1H)-oneor a pharmaceutically acceptable salt, stereoisomer or tautomer thereofto azacitidine is about 1:3 to about 1:20.
 2. The method of claim 1,comprising administration of7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((1r,4r)-4-methoxycyclohexyl)-3,4-dihydropyrazino-[2,3-b]pyrazin-2(1H)-oneor a pharmaceutically acceptable salt, stereoisomer or tautomer thereofin combination with an effective amount of erlotinib to a patient havingadvanced non-small cell lung cancer.
 3. The method of claim 1,comprising administration of7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((1r,4r)-4-methoxycyclohexyl)-3,4-dihydropyrazino-[2,3-b]pyrazin-2(1H)-oneor a pharmaceutically acceptable salt, stereoisomer or tautomer thereofin combination with an effective amount of azacitidine to a patienthaving advanced non-small cell lung cancer.
 4. The method of claim 3,wherein the azacitidine is oral azacitidine.